Modulators of mas-related g-protein receptor x4 and related products and methods

ABSTRACT

Methods are provided for modulating MRGPR X4 generally, or for treating a MRGPR X4 dependent condition more specifically, by contacting the MRGPR X4 or administering to a subject in need thereof, respectively, an effective amount of a compound having the structure of Formula (I). 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n, x, A, Q 1 , Q 2 , Z, R, R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein. Pharmaceutical compositions containing such compounds, as well as to compounds themselves, are also provided.

RELATED APPLICATIONS

This application is related to U.S. Provisional Application Nos.62/825,741 filed Mar. 28, 2019; 62/849,095 filed May 16, 2019;62/864,306 filed Jun. 20, 2019; 62/938,277 filed Nov. 20, 2019;62/955,967 filed Dec. 31, 2019; and 62/959,799 filed Jan. 10, 2020; eachof which are hereby incorporated by reference in their entirety.

BACKGROUND Technical Field

The invention relates to modulators of the Mas-related G-protein coupledreceptor X4, to products containing the same, as well as to methods oftheir use and preparation.

Description of the Related Art

Mas-related G protein receptors (MRGPRs) are a group of orphan receptorswith limited expression in very specialized tissues. Very little isknown about the function of most of these receptors. There are eightrelated receptors in this class expressed in humans, only four of whichhave readily identifiable orthologs in other species (i.e., MRGPR D, E,F and G). The other four receptors (MRGPR X1, X2, X3 and X4) have nocounterpart, based on homology, in species other than human.

BRIEF SUMMARY

This invention is based, in part, on the identification thatfunctionally in mice MRGPR A1 corresponds, at least in part, to thehuman MRGPR X4. These receptors mediate disorders including chronic itch(e.g., pruritus), inflammation disorders, autoimmunity, skin disorders,cardiovascular disease, lung inflammation/COPD, and adverse skinreactions to drugs. More specifically, both MRGPR A1 and MRGPR X4 areexpressed in sensory neurons, skin melanocytes, dendritic cells,polymorphonuclear cells, macrophages, bronchial epithelial cells, lungsmooth muscle and dorsal root ganglia. It has now been identified thatboth MRGPR A1 and MRGPR X4 are receptors for (or sensitive to activationby) circulating bilirubin and its metabolites, and thus are importantfor itch sensation in conditions of elevated bilirubin such ascholestatic pruritus. In addition, MRGPR X4 is activated by multipleadditional components of bile including bile acids and metabolitesthereof and heme metabolites including bilirubin and urobilin. Bileacids and bilirubin are highly elevated in cholestatic pruritus whileurobilin, which is a potent mediator of itch induction in mouse model,and thus may be important for itch sensation in conditions of elevatedurobilin such as uremic pruritus. Thus, modulating MRGPR X4 allows fortreatment of autoimmune diseases such as psoriasis, multiple sclerosis,Steven Johnson's Syndrome, and other chronic itch conditions asexplained in more detail below.

Accordingly, in an embodiment, methods are provided for modulating aMRGPR X4 by contacting the MRGPR X4 with an effective amount of acompound having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein n, x, A, Q₁, Q₂, Z, R, R¹, R², R³, R⁴and R⁵ are as defined below.

In another embodiment, methods are provided for treating a MRGPR X4dependent condition by administering to a subject in need thereof aneffective amount of a compound having the structure of Formula (I), or apharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,or salt thereof.

In more specific embodiments, the MRGPR X4 dependent condition is one ormore of an itch associated condition, a pain associated condition, aninflammation-associated condition, or an autoimmune disorder.

In another embodiment, pharmaceutical compositions are providedcomprising a compound having the structure of Formula (I), or apharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,or salt thereof, in combination with a pharmaceutically acceptableexcipient.

In another embodiment, compounds are provided having one or more of thestructures disclosed herein, or a pharmaceutically acceptable isomer,racemate, hydrate, solvate, isotope, or salt thereof.

In further embodiments, prodrugs and/or metabolites of a compound havingthe structure of Formula (I) are also provided. In the case of prodrugs,a compound (i.e., prodrug) may be administered to a subject which isthen converted in vivo to a compound having the structure of Formula(I). In the case of metabolites, following administration to a subjectof a compound having the structure of Formula (I) such compound may beconverted in vivo to an active metabolite.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows in vitro activation of MRGPR X4 by heme metabolitesbilirubin, biliverdin, urobilin, urobilinogen, and stercobilin.

FIGS. 2A-2B show induction of itch in wild type mice by urobilincompared to vehicle (VEH) (FIG. 2A) and by urobilin, bilirubin, anddeoxycholic acid (FIG. 2B).

FIGS. 3A-3B show bilirubin stability (FIG. 3A) and bilirubin agonism ofMRGPRX4 (FIG. 3B) after 24 hours storage under various temperature andlight storage conditions (time zero (freshly prepared), room temperaturedark, −20° C. dark, room temperature lab light, and room temperature 400nm blue light).

FIGS. 4A-4B show urobilin stability (FIG. 4A) and urobilin agonism ofMRGPRX4 (FIG. 4B) after 24 hours storage under various temperature andlight storage conditions (time zero (freshly prepared), room temperaturedark, −20° C. dark, room temperature lab light, and room temperatureblue light).

DETAILED DESCRIPTION

As mentioned above, the invention relates to modulators of the MRGPR X4,to products containing the same, as well as to methods of their use andpreparation. This invention is based, in part, on the identificationthat in mice MRGPR A1 functionally corresponds to the human MRGPR X4.These receptors mediate disorders including chronic and intermittentitch (e.g., pruritus), inflammation disorders, autoimmunity, skindisorders, and adverse skin reactions to drugs and infectious diseases.More specifically, both MRGPR A1 and MRGPR X4 are expressed in sensoryneurons and dorsal root ganglia. It has now been identified that bothMRGPR A1 and MRGPR X4 are receptors for (or sensitive to activation by)circulating bilirubin and its metabolites, and thus are important foritch sensation in conditions of elevated bilirubin such as cholestaticpruritus and end-stage renal failure. In addition, MRGPR X4 is alsoactivated by bile acids and metabolites thereof, which are also elevatedin cholestatic pruritus. Furthermore, urobilin, an oxidative product ofthe heme metabolite urobilinogen solely excreted by the kidney, is apotent agonist of MRGPRX4 and pruritogen, and thus may be important foritch sensation in conditions of elevated urobilin such as uremicpruritus, kidney disease and end-stage renal failure. Thus, modulatingMRGPR X4 allows for treatment of autoimmune diseases such as psoriasis,multiple sclerosis, Steven Johnson's Syndrome, atopic disorders such asatopic dermatitis and other chronic itch conditions as explained in moredetail below.

MRGPRs appear to be sensory receptors that recognize their externalenvironment to exogenous or endogenous signals/chemicals. Thesereceptors likely respond to multiple chemical ligands/agonists. Forexample MRGPR X4 recognizes bilirubin, bile acids, and urobilin asagonist signals. In certain embodiments, molecules of this inventionmodulate MRGPR X4 by functioning as inverse agonists that are capable ofblocking multiple chemical entities, and/or as competitive antagoniststhat can specifically block individual ligands. In one embodiment, suchmodulations are selective against other MRGPRs, such as MRGPR X1, X2and/or X3.

Accordingly, in one embodiment, methods for modulating a MRGPR X4 areprovided comprising contacting the MRGPR X4 with an effective amount ofcompound having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein:

-   -   n is 0 or 1;    -   x is 0, 1 or 2;    -   A is aryl or heteroaryl;    -   Q₁ and Q₂ are both CR¹⁰, or one of Q₁ or Q₂ is CR¹⁰ and the        other is N;    -   Z is —O—, —S—, —N(R¹¹)—, —CH₂— or —C≡C—;    -   each R¹⁰ is H or alkyl;    -   R is —(CH₂)_(m)C(═O)OR¹², —(CH₂)_(m)NHR¹³, —(C═O)NR¹⁴R¹⁵,        —CH₂OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic        acid isostere;    -   m is 0 or 1;    -   R¹¹, R¹² and R¹³ are the same or different and individually H or        alkyl;    -   R¹⁴ is H and R¹⁵ is H, —SO₂CH₃, carbocycle, heterocyle, or alkyl        substituted with 0, 1, 2 or 3 substituents selected from —OH,        —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle, or        heterocycyle, wherein R′ and R″ are individually H or alkyl, or    -   R¹⁴ and R¹⁵ are taken together with the nitrogen atom to which        they are attached to form heterocycle;    -   R¹ is H or alkyl;    -   R² is halo, cyano, amino, alkyl, alkoxy, carbocycle or        heterocycle;    -   R³, R⁴ and R⁵ are the same or different and either absent or,        when present, cyano, nitro, halogen, alkyl, haloalkyl,        cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl,        carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or    -   any two R and R² taken together with the atoms to which they are        attached form heterocycle;    -   any two R³, R⁴, R⁵ and R¹, taken together with the atoms to        which they are attached form carbocycle or heterocycle;    -   and wherein each occurrence of carbocycle or heterocycle is        substituted with 0, 1, 2 or 3 substituents individually selected        from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, carbocycle, or heterocycle.

“Modulating” MRGPR X4 means that the compound interacts with the MRGPRX4 in a manner such that it functions as an inverse agonist to thereceptor, and/or as a competitive antagonist to the receptor. In oneembodiment, such modulation is partially or fully selective againstother MRGPRs, such as MRGPR X1, X2 and/or X3.

“MRGPR” refers to one or more of the Mas-related G protein coupledreceptors, which are a group of orphan receptors with limited expressionin very specialized tissues (e.g., in sensory neurons and dorsal rootganglia) and barrier tissues. There are eight related receptors in thisclass expressed in humans, only 4 of which have readily identifiableorthologs in other species (i.e., MRGPR D, E, F and G). The other fourreceptors (MRGPR X1, X2, X3 and X4) have no counterpart, based onhomology, in non-human species.

“Effective amount” refers to a quantity of a specified agent sufficientto achieve a desired effect in a subject being treated with that agent.Ideally, an effective amount of an agent is an amount sufficient toinhibit or treat the disease without causing substantial toxicity in thesubject. The effective amount of an agent will be dependent on thesubject being treated, the severity of the affliction, and the manner ofadministration of the pharmaceutical composition. Methods of determiningan effective amount of the disclosed compound sufficient to achieve adesired effect in a subject will be understood by those of skill in theart in light of this disclosure.

“Alkyl” means a saturated or unsaturated straight chain or branchedalkyl group having from 1 to 8 carbon atoms, in some embodiments from 1to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and insome embodiments from 1 to 3 carbon atoms. Examples of saturatedstraight chain alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. An unsaturated alkyl includes alkenyl andalkynyl as defined below.

“Alkenyl” means a straight chain or branched alkenyl group having from 2to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in someembodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons that containat least one carbon-carbon double bond. Examples of lower alkenyl groupsinclude, but are not limited to, vinyl, propenyl, butenyl, pentenyl, andhexenyl.

“Alkynyl” means a straight chain or branched alkynyl group having from 2to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in someembodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons that containat least one carbon-carbon triple bond.

Examples of alkynyl groups include, but are not limited to, ethynyl,propynyl, butynyl, pentynyl, and hexynyl.

“Halo” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

“Hydroxy” refers to —OH.

“Cyano” refers to —CN.

Amino refers to —NH₂, —NHalkyl or N(alkyl)₂, wherein alkyl is as definedabove. Examples of amino include, but are not limited to —NH₂, —NHCH₃,—N(CH₃)₂, and the like.

“Haloalkyl” refers to alkyl as defined above with one or more hydrogenatoms replaced with halogen. Examples of lower haloalkyl groups include,but are not limited to, —ClF₃, —CHF₂, and the like.

“Alkoxy” refers to alkyl as defined above joined by way of an oxygenatom (i.e., —O-alkyl). Examples of alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy,sec-butoxy, tert-butoxy, and the like.

“Haloalkoxy” refers to haloalkyl as defined above joined by way of anoxygen atom (i.e., —O-haloalkyl). Examples of lower haloalkoxy groupsinclude, but are not limited to, —OCF₃, and the like.

“Cycloalkyl” refers to alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like.

“Aryl” groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Representative aryl groups include, but are not limited to,phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments,aryl groups contain 6-14 carbons in the ring portions of the groups. Theterms “aryl” and “aryl groups” include fused rings wherein at least onering, but not necessarily all rings, are aromatic, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like). In one embodiment, aryl is phenyl or naphthyl, and in anotherembodiment aryl is phenyl.

“Carbocycle” refers to alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring maygive rise to aromaticity. In one embodiment, carbocycle includescycloalkyl as defined above. In another embodiment, carbocycle includesaryl as defined above.

“Heterocycle” refers to aromatic and non-aromatic ring moietiescontaining 3 or more ring members, of which one or more is a heteroatomsuch as, but not limited to, N, O, S, or P. In some embodiments,heterocyclyl include 3 to 20 ring members, whereas other such groupshave 3 to 15 ring members. At least one ring contains a heteroatom, butevery ring in a polycyclic system need not contain a heteroatom. Forexample, a dioxolanyl ring and a benzdioxolanyl ring system(methylenedioxyphenyl ring system) are both heterocyclyl groups withinthe meaning herein.

Heterocyclyl groups also include fused ring species including thosehaving fused aromatic and non-aromatic groups. A heterocyclyl group alsoincludes polycyclic ring systems containing a heteroatom such as, butnot limited to, quinuclidyl, and also includes heterocyclyl groups thathave substituents, including but not limited to alkyl, halo, amino,hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one ofthe ring members. A heterocyclyl group as defined herein can be aheteroaryl group or a partially or completely saturated cyclic groupincluding at least one ring heteroatom. Heterocyclyl groups include, butare not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl,dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl,thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

“Heteroaryl” refers to aromatic ring moieties containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl,pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl,triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.

“Carboxylic acid isostere” refers to a group that serves as a surrogateto a carboxylic acid group (i.e., —COOH). Use of a carboxylic acidisostore may be preferable to a carboxylic acid group for a number orreasons, including greater selectivity, reduced side effects, decreasedtoxicity, improved pharmacokinetics, increased stability, and/orsimplified synthesis. Carboxylic acid isosteres include hydroxamicacids, acylcyanamides, sulfonamides, phosphonic acids, phosphinc acids,cyanoacetamides, sulfonates, sulfonamides, acylsulfonamides,arylsulfonamides, sulfonylureas, tetrazoles, thiazolidinediones,oxazolidinediones, isoxazoles, isothiazoles, squaric acids,3-hydroxyquinolin-2-ones, 4-hydroxyquinolin-2-ones,5-oxo-1,2,4-oxadiazoles, 5-oxo-1,2,4-thiadiazoles,5-thioxo-1,2,4-oxadiazoles, hydroxyisoxazoles, phenols, tetramic acids,tetronic acids, cyclopentane-1,3-diones, 6-hydroxy-1,3-dioxin-4ones,3-hydroxypyridin-4(1H)-ones, and oxadiazolones.

In an embodiment, a carboxylic acid isostere may be acyclic and have oneof the following structures (wherein R^(a) is alkyl, carbocycle, orheterocycle, wherein each of carbocycle and heterocycle may be singly ormultiply substituted with R²):

In another embodiment, a carboxylic acid isostere may be cyclic and haveone of the following structures:

“Isomer” is used herein to encompass all chiral, diastereomeric orracemic forms of a structure, unless a particular stereochemistry orisomeric form is specifically indicated. Such compounds can be enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be synthesized so as to be substantially free of their enantiomericor diastereomeric partners, and these are all within the scope ofcertain embodiments of the invention. The isomers resulting from thepresence of a chiral center comprise a pair of nonsuperimposable-isomersthat are called “enantiomers.” Single enantiomers of a pure compound areoptically active (i.e., they are capable of rotating the plane of planepolarized light and designated R or S).

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.For example, the isolated isomer may be at least about 80%, at least 80%or at least 85% pure by weight. In other embodiments, the isolatedisomer is at least 90% pure or at least 98% pure, or at least 99% pureby weight.

“Substantially enantiomerically or diastereomerically” pure means alevel of enantiomeric or diastereomeric enrichment of one enantiomerwith respect to the other enantiomer or diastereomer of at least about80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%,99.5% or 99.9%.

The terms “racemate” and “racemic mixture” refer to an equal mixture oftwo enantiomers. A racemate is labeled “(±)” because it is not opticallyactive (i.e., will not rotate plane-polarized light in either directionsince its constituent enantiomers cancel each other out). All compoundswith an asterisk (*) adjacent to a tertiary or quaternary carbon areoptically active isomers, which may be purified from the respectiveracemate and/or synthesized by appropriate chiral synthesis.

A “hydrate” is a compound that exists in combination with watermolecules. The combination can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form; that is, a compound in a water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is similar to a hydrate except that a solvent other thatwater is present. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form; that is,a compound in a solvent solution, while it may be solvated, is not asolvate as the term is used herein.

“Isotope” refers to atoms with the same number of protons but adifferent number of neutrons, and an isotope of a compound of Formula(I) includes any such compound wherein one or more atoms are replaced byan isotope of that atom. For example, carbon 12, the most common form ofcarbon, has six protons and six neutrons, whereas carbon 13 has sixprotons and seven neutrons, and carbon 14 has six protons and eightneutrons. Hydrogen has two stable isotopes, deuterium (one proton andone neutron) and tritium (one proton and two neutrons). While fluorinehas a number of isotopes, fluorine-19 is longest-lived. Thus, an isotopeof a compound having the structure of Formula (I) includes, but notlimited to, compounds of Formula (I) wherein one or more carbon 12 atomsare replaced by carbon-13 and/or carbon-14 atoms, wherein one or morehydrogen atoms are replaced with deuterium and/or tritium, and/orwherein one or more fluorine atoms are replaced by fluorine-19.

“Salt” generally refers to an organic compound, such as a carboxylicacid or an amine, in ionic form, in combination with a counter ion. Forexample, salts formed between acids in their anionic form and cationsare referred to as “acid addition salts”. Conversely, salts formedbetween bases in the cationic form and anions are referred to as “baseaddition salts.”

The term “pharmaceutically acceptable” refers an agent that has beenapproved for human consumption and is generally non-toxic. For example,the term “pharmaceutically acceptable salt” refers to nontoxic inorganicor organic acid and/or base addition salts (see, e.g., Lit et al., SaltSelection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986)(incorporated by reference herein).

Pharmaceutically acceptable base addition salts of compounds of theinvention include, for example, metallic salts including alkali metal,alkaline earth metal, and transition metal salts such as, for example,calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceuticallyacceptable base addition salts also include organic salts made frombasic amines such as, for example, N,N′dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of inorganic acidsinclude hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids,examples of which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic,embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic,p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,alginic, βhydroxybutyric, salicylic, -galactaric, and galacturonic acid.

Although pharmaceutically unacceptable salts are not generally useful asmedicaments, such salts may be useful, for example as intermediates inthe synthesis of compounds having the structure of Formula I, forexample in their purification by recrystallization.

In another embodiment, a method of treating a subject having a MRGPR X4dependent condition is provided, the method comprising administering tothe subject a pharmaceutically effective amount of a compound having thestructure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein:

-   -   n is 0 or 1;    -   x is 0 or 1;    -   A is aryl or heteroaryl;    -   Q₁ and Q₂ are both CR¹⁰, or one of Q₁ or Q₂ is CR¹⁰ and the        other is N;    -   Z is —O—, —S—, —N(R¹¹)—, —CH₂— or —C≡C—;    -   each R¹⁰ is H or alkyl;    -   R is —(CH₂)_(m)C(═O)OR¹², —(CH₂)_(m)NHR¹³, —(C═O)NR¹⁴R¹⁵,        —CH₂OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic        acid isostere;    -   m is 0 or 1;    -   R¹¹, R¹² and R¹³ are the same or different and individually H or        alkyl;    -   R¹⁴ is H and R¹⁵ is H, —SO₂CH₃, carbocycle, heterocyle, or alkyl        substituted with 0, 1, 2 or 3 substituents selected from —OH,        —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle, or        heterocycyle, wherein R′ and R″ are individually H or alkyl, or    -   R¹⁴ and R¹⁵ are taken together with the nitrogen atom to which        they are attached to form heterocycle;    -   R¹ is H or alkyl;    -   R² is halo, cyano, alkyl, alkoxy, carbocycle or heterocycle;    -   R³, R⁴ and R⁵ are the same or different and either absent or,        when present, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy,        haloalkoxy, carbocycle, heterocycle, —O-carbocycle or        —O-heterocycle, or    -   any two R and R² taken together with the atoms to which they are        attached form heterocycle;    -   any two R³, R⁴, R⁵ and R¹⁰, taken together with the atoms to        which they are attached form carbocycle or heterocycle;    -   and wherein each occurrence of carbocycle or heterocycle is        substituted with 0, 1, 2 or 3 substituents individually selected        from halogen, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,        carbocycle, or heterocycle.

As used herein, the phrase “MRGPR X4 dependent condition” means acondition where the activation, over sensitization, or desensitizationof MRGPR X4 by a natural or synthetic ligand initiates, mediates,sustains, or augments a pathological condition. For example, it is knownthat some itch or pain sensations are caused by elevated bilirubin andits metabolites or bile acids in patients suffering from pruritus,atopic or other autoimmune or inflammatory diseases. It has been foundthat MRGPR X4 is sensitive to (or activated by) bilirubin and itsmetabolites, including urobilin, or bile acids. Without limited bytheory, it is to be understood that by modulating MRGPR X4, the itch orpain sensations can be eased.

In some embodiments, the MRGPR X4 dependent condition is a conditionthat is caused by the activation of MRGPR X4 by a bile acid. As usedherein, the term “bile acid” includes primary bile acids (e.g., cholicacid, chenodeoxycholic acid), conjugated bile acids, also referred to asbile salts (e.g., taurocholic acid, glycocholic acid,taurochenodeoxycholic acid, glycochenodeoxycholic acid), secondary bileacids (e.g., deoxycholic acid, lithocholic acid), and bile acid analogs.In some embodiments, a bile acid analog is a farnesoid X-receptor (FXR)agonist. Thus, the compounds of the present disclosure may be used fortreating an MRGPR X4 dependent condition caused by activation of MRGPRX4 by a bile acid and that would benefit from modulating MRGPR X4.

In some embodiments, the MRGPR X4 dependent condition is an itchassociated condition, a pain associated condition, an autoimmunecondition, or an autoimmune or inflammatory disorder.

As used herein, the phrase “itch associated condition” means pruritus(including acute and chronic pruritus) associated with any condition.The itch sensation can originate, e.g., from the peripheral nervoussystem (e.g., dermal or neuropathic itch) or from the central nervoussystem (e.g., neuropathic, neurogenic or psychogenic itch). Thus, in oneembodiment, the method of present invention is provided to treat an itchassociated condition, such as chronic itch; cholestatic pruritus;contact dermatitis; Allergic blepharitis; Anemia; Atopic dermatitis;Bullous pemphigoid; Candidiasis; Chicken pox; Cholestasis; end-stagerenal failure; hemodialysis; Contact dermatitis, Atopic Dermatitis;Dermatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidroticdermatitis; Ectopic eczema; Erythrasma; Folliculitis; Fungal skininfection; Hemorrhoids; Herpes; HIV infection; Hodgkin's disease;Hyperthyroidism; Iron deficiency anemia; Kidney disease; Leukemia,porphyrias; Liver disease, including primary biliary cholangitis,primary sclerosing cholangitis, Alagille syndrome, Progressive familialintrahepatic cholestasis, Intrahepatic cholestasis of pregnancy,nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease(NAFLD), biliary atresia, chronic B hepatitis, drug-chronic viralhepatitis, induced liver injury (DILI), liver fibrosis, cholestaticliver disease, and alcoholic liver disease; Lymphoma; Malignancy;Multiple myeloma; Neurodermatitis; Onchocerciasis; Paget's disease;Pediculosis; Polycythemia rubra vera; Lichen Planus; Lichen Sclerosis;Pruritus ani; Pseudorabies; Psoriasis; Rectal prolapse; Scabies;Schistosomiasis; Scleroderma, Severe stress, Stasia dermatitis;Swimmer's itch; Thyroid disease; Tinea cruris; Uremic Pruritus; Rosacea;Cutaneous amyloidosis; Scleroderma; Acne; wound healing; ocular itch;and Urticaria.

As used herein, the phrase “pain associated condition” means any paindue to a medical condition. Thus, in one embodiment, the method ofpresent invention is provided to treat a pain associated condition, suchas Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, AnkylosingSpondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic CerebralPalsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain,Behcet's Disease (Syndrome), Burning Mouth Syndrome, Bursitis, CancerPain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome,Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease,Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain(CFAP), Chronic Pain, Chronic Pancreatitis, Collapsed Lung(Pneumothorax), Complex Regional Pain Syndrome (RSD), CornealNeuropathic Pain, Crohn's Disease, Degenerative Disc Disease, Dercum'sDisease, Dermatomyositis, Diabetic Peripheral Neuropathy (DPN),Dystonia, Ehlers-Danlos Syndrome (EDS), Endometriosis,Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia, Fibromyalgia,Gout, Headaches, Herniated disc, Hydrocephalus, Intercostal Neuraligia,Interstitial Cystitis, Irritable Bowel syndrome (IBS), JuvenileDermatositis (Dermatomyositis), Knee Injury, Leg Pain, LoinPain-Haematuria Syndrome, Lupus, Lyme Disease, Medullary Sponge Kidney(MSK), Meralgia Paresthetica, Mesothelioma, Migraine, Musculoskeletalpain, Myofascial Pain, Myositis, Neck Pain, Neuropathic Pain, OccipitalNeuralgia, Osteoarthritis, Paget's Disease, Parsonage Turner Syndrome,Pelvic Pain, Peripheral Neuropathy, Phantom Limb Pain, Pinched Nerve,Polycystic Kidney Disease, Polymyalgia Rhuematica, Polymyositis,Porphyria, Post Herniorraphy Pain Syndrome, Post Mastectomy, PainSyndrome, Post Stroke Pain, Post Thorocotomy Pain Syndrome, PostherpeticNeuralgia (Shingles), Post-Polio Syndrome, Primary Lateral Sclerosis,Psoriatic Arthritis, Pudendal Neuralgia, Radiculopathy, Raynaud'sDisease, Rheumatoid Arthritis (RA), Sacroiliac Joint Dysfunction,Sarcoidosi, Scheuemann's Kyphosis Disease, Sciatica, Scoliosis, Shingles(Herpes Zoster), Sjogren's Syndrome, Spasmodic Torticollis, Sphincter ofOddi Dysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal CordInjury, Spinal Stenosis, Syringomyelia, Tarlov Cysts, TransverseMyelitis, Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis,Vascular Pain and Vulvodynia.

As used herein, the term “autoimmune disorder”, or “inflammatorydisorder” means a disease or disorder arising from and/or directedagainst an individual's own tissues or organs, or a co-segregate ormanifestation thereof, or resulting condition therefrom. Typically,various clinical and laboratory markers of autoimmune diseases may existincluding, but not limited to, hypergammaglobulinemia, high levels ofautoantibodies, antigen-antibody complex deposits in tissues, clinicalbenefit from corticosteroid or immunosuppressive treatments, andlymphoid cell aggregates in affected tissues. Thus, in one embodiment,the method of present invention is provided to treat an autoimmunedisorder, such as chronic inflammation, Multiple Sclerosis, StevenJohnson's Syndrome, appendicitis, bursitis, colitis, cystitis,dermatitis, phlebitis, reflex sympathetic dystrophy/complex regionalpain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acnevulgaris, reactive airway disorder, asthma, airway infection,autoinflammatory disease, celiac disease, chronic prostatitis,diverticulitis, glomerulonephritis, hidradenitis suppurativa,hypersensitivities, intestinal disorder, epithelial intestinal disorder,inflammatory bowel disease, irritable bowel syndrome, colitis,interstitial cystitis, otitis, pelvic inflammatory disease, endometrialpain, reperfusion injury, rheumatic fever, rheumatoid arthritis,sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronicobstructive pulmonary disease, cardiovascular disease, and vasculitis.

As used herein, the term “administration” refers to providing acompound, or a pharmaceutical composition comprising the compound asdescribed herein. The compound or composition can be administered byanother person to the subject or it can be self-administered by thesubject. Non-limiting examples of routes of administration are oral,parenteral (e.g., intravenous), or topical.

As used herein, the term “treatment” refers to an intervention thatameliorates a sign or symptom of a disease or pathological condition. Asused herein, the terms “treatment”, “treat” and “treating,” withreference to a disease, pathological condition or symptom, also refersto any observable beneficial effect of the treatment. The beneficialeffect can be evidenced, for example, by a delayed onset of clinicalsymptoms of the disease in a susceptible subject, a reduction inseverity of some or all clinical symptoms of the disease, a slowerprogression of the disease, a reduction in the number of relapses of thedisease, an improvement in the overall health or well-being of thesubject, or by other parameters well known in the art that are specificto the particular disease. A prophylactic treatment is a treatmentadministered to a subject who does not exhibit signs of a disease orexhibits only early signs, for the purpose of decreasing the risk ofdeveloping pathology. A therapeutic treatment is a treatmentadministered to a subject after signs and symptoms of the disease havedeveloped.

As used herein, the term “subject” refers to an animal (e.g., a mammal,such as a human). A subject to be treated according to the methodsdescribed herein may be one who has been diagnosed with a MRGPR X4dependent condition, such as an itch associated condition, a painassociated condition, or an autoimmune disorder. Diagnosis may beperformed by any method or technique known in the art. One skilled inthe art will understand that a subject to be treated according to thepresent disclosure may have been subjected to standard tests or may havebeen identified, without examination, as one at risk due to the presenceof one or more risk factors associated with the disease or condition.

In another embodiment, the method of treating a subject having a MRGPRX4 dependent condition (e.g., an itch associated condition, a painassociated condition, an autoimmune condition, or an autoimmunedisorder) described herein further comprises administering to thesubject a pharmaceutically effective amount of a second therapeuticagent. In one embodiment, the itch associated condition is a liverdisease. In one embodiment, the second therapeutic agent is a liverdisease therapeutic agent. In one embodiment, the liver diseasetherapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholicacid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate,bezafibrate, metronidazole, methotrexate, colchicine, metformin,betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, aperoxisome proliferator-activated receptor (PPAR) agonist, a thyroidhormone receptor beta (TRβ) agonist, or any combination thereof.

Examples of FXR agonists that may be used in the methods describedherein include obeticholic acid, Turofexorate isopropyl (WAY-362450),3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole(GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101,altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl,fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor(GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023,AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480,INV-33, RDX023-02, or any combination thereof. In one embodiment, a FXRagonist is a bile acid or analog thereof (e.g., obeticholic acid,INT-767, INT-787, BAR502, hedragonic acid or BAR704) or a non-bile acidagonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor, GW4064,Turofexorate isopropyl, fexaramine, PX20606 (PX-102), TERN-101,altenusin, silymarin, silybin, EYP-001, RDX023-2, AGN-242266, HPG-1860,MET-409, EP-024297, M-480, or cafestol).

In one embodiment, a PPAR agonist is a PPAR-alpha agonist, a PPAR-gammaagonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPARalpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPARalpha/gamma/delta pan agonist.

Examples of PPAR alpha agonists that may be used in the methodsdescribed herein include fenofibrate, ciprofibrate, pemafibrate,gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid,nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate,tocofibrate, and SRI 0171.

Examples of PPAR gamma agonists that may be used in the methodsdescribed herein include rosiglitazone, pioglitazone,deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405,CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, andALL-4.

Examples of PPAR delta agonists that may be used in the methodsdescribed herein include GW501516 (endurabol or({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (seladelpar or{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceticacid), GW0742([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy] acetic acid), L165041, HPP-593, and NCP-1046.

Examples of PPAR alpha/gamma agonists that may be used in the methodsdescribed herein include saroglitazar, aleglitazar, muraglitazar,tesaglitazar, and DSP-8658.

Examples of PPAR alpha/delta agonists that may be used in the methodsdescribed herein include elafibranor and T913659.

Examples of PPAR gamma/delta agonists that may be used in the methodsdescribed herein include a conjugated linoleic acid (CLA) and T3D-959.

Examples of PPAR alpha/gamma/delta agonists that may be used in themethods described herein include IVA337 (lanifibranor), TTA(tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate,lobeglitazone,2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoicacid (MHY2013), and CS038.

Examples of thyroid hormone receptor beta agonists that may be used inthe methods described herein include sobetirome, eprotirome, GC-24,MGL-3196, MGL-3745, VK-2809, KB141[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], andMB07811(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane).

The second therapeutic agent may be administered simultaneously,separately, or sequentially with the compounds of the presentdisclosure. If administered simultaneously, the second therapeutic agentand compound of the present disclosure may be administered in separatedosage forms or in the same dosage form.

In another embodiment, a method of treating a subject having an itchassociated condition is provided, the method comprising administering tothe subject a pharmaceutically effective amount of a compound having thestructure of Formula (I) or pharmaceutically acceptable isomer,racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceuticalcomposition thereof. In one embodiment, the itch associated condition ischolestatic pruritus, uremic pruritus, atopic dermatitis, dry skin,psoriasis, contact dermatitis, or eczema.

In one embodiment of Formula (I), n is 1, R¹ is H, Z is 0, R is—C(═O)OR¹², and the compound has the structure of Formula (II):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹²are as defined above.

In one embodiment of Formula (I), n is 0, Z is O and the compound hasthe structure of Formula (III):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹²are as defined above.

In one embodiment of Formula (II), x is 0 and the and the compound hasthe of Formula (IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein A, Q₁, Q₂, R³, R⁴, R⁵ and R¹² are asdefined above.

In one embodiment of Formula (II), x is 1 and the compound has thestructure of Formula (V):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹² areas defined above.

In one embodiment of Formula (III), x is 0 and the compound has thestructure of Formula (VI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R³, R⁴, R⁵ and R¹² areas defined above.

In one embodiment of Formula (III), x is 1 and the compound has thestructure of Formula (VII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹²are as defined above.

In another embodiment, when R¹² is hydrogen in each of Formulas (II)through (VII) the resulting carboxylic acid group (—COOH) is replacedwith a carboxylic acid isostere as defined herein.

In one embodiment of Formula (I), n is 1, R¹ is H, Z is O, R is—(C═O)NHR¹⁵, —CH₂OH, —CH₂NH₂ or —CN, and the compound has the structureof Formula (VIII), (IX), (X) or (XI), respectively:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹⁵are as defined above.

In one embodiment of Formula (I), n is 0, Z is 0, R is —(C═O)NHR¹⁵,—CH₂OH, —CH₂NH₂ or —CN, and the compound has the structure of Formula(XII), (XIII), (XIV) or (XV), respectively:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, A, Q₁, Q₂, R², R³, R⁴, R⁵ and R¹are as defined above.

In one embodiment of Formula (I), Z is —S—, —N(R¹¹)—, —CH₂— or —C≡C— andthe compound has the structure of Formula (XVI), (XVII), (XVIII) or(IX), respectively:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein n, x, A, Q₁, Q₂, R, R¹, R², R³, R⁴, R⁵and R¹¹ are as defined above.

In one embodiment of any one of Formulas (I) through (XIX), A is aryl.

In one embodiment of any one of Formulas (I) through (XIX), A is phenyl.

In one embodiment of any one of Formulas (I) through (XIX), A is phenylwith the following points of attachment:

In one embodiment of any one of Formulas (I) through (XIX), A isheteroaryl.

In one embodiment of any one of Formulas (I) through (XIX), A ispyridine or pyrazine.

In one embodiment of any one of Formulas (I) through (XIX), A ispyridine or pyrazine with the following points of attachment,respectively:

In one embodiment of any one of Formulas (I) through (XIX), A is furan,thiophene or isoxazole.

In one embodiment of any one of Formulas (I) through (XIX), A is furan,thiophene or isoxazole with the following points of attachment,respectively:

In one embodiment of any one of Formulas (I) through (XIX), Q₁ and Q₂are both CH.

In one embodiment of any one of Formulas (I) through (XIX), Q₁ is CH andQ₂ is N.

In one embodiment of any one of Formulas (I) through (XIX), Q₁ is N andQ₂ is CH.

In one embodiment of any one of Formulas (I) through (XIX), R¹ ishydrogen.

In one embodiment of any one of Formulas (I) through (XIX), R¹ is alkyl.

In one embodiment of any one of Formulas (I) through (XIX), R¹ ismethyl.

In one embodiment of Formula (I), the compound has the structure ofFormula (XX):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein x, R², R³, R⁴, R⁵ and R¹² are asdefined above.

In one embodiment of Formula (I), the compound has the structure ofFormula (XXI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein R³, R⁴, R⁵ and R¹² are as definedabove.

In one embodiment of Formula (I), the compound has the structure ofFormula (XXII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein R², R³, R⁴, R⁵ and R¹² are as definedabove.

In another embodiment, when R¹² in hydrogen in each of Formulas (XX)through (XXII) above the resulting carboxylic acid group (—COOH) isreplaced with a carboxylic acid isostere as defined herein.

In one embodiment of Formula (I), the compound has the structure ofFormula (XXIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein R³, R⁴ and R⁵ are as defined above.

In one embodiment of Formula (I), the compound has the structure ofFormula (XXIV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein R², R³, R⁴ and R⁵ are as definedabove.

In another embodiment, the carboxylic acid group (—COOH) of each ofFormulas (XXIII) and (XXIV) above is replaced with a carboxylic acidisostere as defined herein.

In one embodiment of any one of Formulas (I) through (XXIV), n is 0.

In one embodiment of any one of Formulas (I) through (XXIV), n is 1.

In one embodiment of any one of Formulas (I) through (XXIV), x is 0.

In one embodiment of any one of Formulas (I) through (XXIV), x is 1.

In one embodiment of any one of Formulas (I) through (XXIV), x is 2.

In one embodiment of any one of Formulas (I) through (XXIV), A is aryl.

In one embodiment of any one of Formulas (I) through (XXIV), A isheteroaryl.

In one embodiment of any one of Formulas (I) through (XXIV), Z is —O—.

In one embodiment of any one of Formulas (I) through (XXIV), Z is —S—.

In one embodiment of any one of Formulas (I) through (XXIV), Z is—N(R¹¹)—

In one embodiment of any one of Formulas (I) through (XXIV), Z is —CH₂—.

In one embodiment of any one of Formulas (I) through (XXIV), Z is or—C≡C—.

In one embodiment of any one of Formulas (I) through (XXIV), R is—(CH₂)_(m)C(═O)OR¹².

In one embodiment of any one of Formulas (I) through (XXIV), R is—(CH₂)_(m)NHR¹³.

In one embodiment of any one of Formulas (I) through (XXIV), R is—(C═O)NR¹⁴R¹⁵.

In one embodiment of any one of Formulas (I) through (XXIV), R is—CH₂OH.

In one embodiment of any one of Formulas (I) through (XXIV), R is —CN.

In one embodiment of any one of Formulas (I) through (XXIV), R ishaloalkyl.

In one embodiment of any one of Formulas (I) through (XXIV), R iscarbocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R isheterocycle.

In one embodiment of any one of Formulas (I) through (XXIV), m is 0.

In one embodiment of any one of Formulas (I) through (XXIV), m is 1.

In one embodiment of any one of Formulas (I) through (XXIV), R¹⁴ is Hand R¹⁵ is H, —SO₂CH₃, carbocycle, heterocyle, or alkyl substituted with0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH,C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle, or heterocycle, wherein R′ andR″ are individually H or alkyl.

In one embodiment of any one of Formulas (I) through (XXIV), R¹⁴ and R¹⁵are taken together with the nitrogen atom to which they are attached toform heterocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R¹ is H.

In one embodiment of any one of Formulas (I) through (XXIV), R¹ isalkyl.

In one embodiment of any one of Formulas (I) through (XXIV), R² is halo.

In one embodiment of any one of Formulas (I) through (XXIV), R² iscyano.

In one embodiment of any one of Formulas (I) through (XXIV), R² isamino.

In one embodiment of any one of Formulas (I) through (XXIV), R² isalkyl.

In one embodiment of any one of Formulas (I) through (XXIV), R² isalkoxy.

In one embodiment of any one of Formulas (I) through (XXIV), R² iscarbocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R² isheterocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R³, R⁴ andR⁵ are the same or different and either absent or, when present, cyano,cyanoalkyl, nitro, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy,—(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or—O-heterocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R³, R⁴ andR⁵ are the same or different and either absent or, when present, cyano,nitro, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.

In one embodiment of any one of Formulas (I) through (XXIV), R³, R⁴ andR⁵ are the same or different and either absent or, when present, —CN,—NO₂, —F, —Cl, —Br, —CH₃, —CF₃, —CHF₂, —C(CH₃)₃, —OCH₃, or —OCF₃.

In one embodiment of any one of Formulas (I) through (XXIV), any two ofR³, R⁴ and R⁵ taken together with the atoms to which they are attachedform carbocycle or heterocycle which is unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from halogen,hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle,or heterocycle.

In one embodiment of any one of Formulas (I) through (XXIV), R³ and R⁴taken together with the atoms to which they are attached formheterocycle as depicted below which is unsubstituted or substituted with1, 2 or 3 substituents independently selected from halogen, hydroxyl,oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, orheterocycle:

In one embodiment of any one of Formulas (I) through (XXIV), R³ and R⁴taken together with the atoms to which they are attached form carbocycleas depicted below which is unsubstituted or substituted with 1, 2 or 3substituents independently selected from halogen, oxo, halo, alkyl,haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle:

Representative compounds of Formula (I), as well as Formulas (II)through (XXIV) as applicable, include any one of the compounds listed inTable A below, as well as a pharmaceutically acceptable isomer,racemate, hydrate, solvate, isotope, or salt thereof. To this end,representative compounds are identified herein by their respective“Compound Number”, which is sometimes abbreviated as “Compound No.” or“Cpd. No.”

TABLE A Representative Compounds Cpd. No. Structure 1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

1-45

1-46

1-47

1-48

1-49

1-50

1-51

1-52

1-53

1-54

1-55

1-56

1-57

1-58

1-59

1-60

1-61

1-62

1-63

1-64

1-65

1-66

1-67

1-68

1-69

1-70

1-71

1-72

1-73

1-74

1-75

1-76

1-77

1-78

1-79

1-80

1-81

1-82

1-83

1-84

1-85

1-86

1-87

1-88

1-89

1-90

1-91

1-92

1-94

1-95

1-96

1-97

1-98

1-99

1-100

1-101

1-102

1-103

1-108

1-109

1-110

1-112

1-113

1-114

1-115

1-116

1-117

1-118

1-119

1-120

1-121

1-122

1-123

1-124

1-125

1-126

1-127

1-128

1-129

1-130

1-131

1-132

1-133

1-134

1-135

1-136

1-137

1-138

1-139

1-140

1-141

1-142

1-143

1-144

1-145

1-146

1-147

1-148

1-149

1-150

1-151

1-152

1-153

1-154

2-1

2-2

2-3

2-4

3-1

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

4-10

4-11

4-12

4-13

4-14

4-15

4-16

4-17

4-18

4-19

4-20

4-21

4-22

4-23

4-24

4-25

4-26

4-27

4-28

4-29

5-1

5-2

6-1

7-1

8-1

8-2

8-3

8-4

9-1

9-2

9-3

10-1

11-1

12-1

12-2

12-3

12-4

13-1

14-1

15-1

16-1

16-2

17-1

17-2

17-3

17-4

17-5

17-6

17-7

17-8

17-9

17-10

17-11

17-12

17-13

17-14

17-15

17-16

31-2

32-1

32-2

32-3

32-4

32-5

33-1

33-2

33-3

33-4

34-1

35-1

36-1

37-1

38-1

39-1

40-1

41-1

41-2

42-1

42-2

42-3

43-1

44-1

45-1

45-2

46-1

47-1

48-1

49-1

50-1

52-1

52-2

52-3

52-4

52-5

52-6

52-7

52-8

52-9

52-10

52-11

52-12

52-13

52-14

52-15

52-16

52-17

52-18

52-19

52-20

52-21

52-22

52-23

52-24

52-25

52-26

52-27

52-28

53-1

53-2

54-1

54-2

54-3

54-4

54-5

54-6

54-7

54-8

54-9

54-10

54-11

54-12

55-1

55-2

55-3

56-1

56-2

57-1

58-1

58-2

59-1

60-1

61-1

62-1

63-1

64-1

65-1

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydratesolvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In a more specific embodiment, the compound has the following structure,or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof:

In another embodiment, certain compounds of Formula (I), as well asFormulas (II) through (XXIV), as applicable, can have their carboxylicacid moiety substituted for a carboxylic acid isostere group, asdescribed herein. Representative carboxylic acid isostere compoundsderived from the representative compounds listed below are presented inTable B.

To this end, the carboxylic acid isostere groups used for compounds ofTable B are as follows:

TABLE B Representative Carboxylic Acid Isostere Compounds Cpd. No.Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

In other embodiments, prodrugs and/or metabolites of compounds ofFormula (I), as well as Formulas (II) through (XXIV), are provided.

Thus, in one embodiment, prodrugs of a compound of the invention areprovided, which upon administration to a subject, undergo chemicalconversion by metabolic or other physiological processes to becomeactive pharmacological substances. Conversion by metabolic or otherphysiological processes includes, without limitation, enzymatic (e.g.,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Accordingly, a “prodrug” is a substance that, upon administration to asubject, is converted in vivo by the action of biochemicals within thesubject's body, such as enzymes, to an active pharmaceutical ingredient.Examples of prodrugs include esters of carboxylic acid groups, which canbe hydrolyzed by endogenous esterases as are found in the bloodstream ofhumans and other mammals. In one embodiment, substances are providedthat can be administered to a subject which are then converted withinthe subject's body to provide a compound having the structure of Formula(I), or any of Formulas (II) through (XXIV).

In this regard, prodrugs of carboxylic acids are typically esters andamides, which can readily be made from the corresponding carboxylic acidby known techniques. For example, in one embodiment, prodrugs may begenerated by converting the carboxylic acid moiety of the compounds ofFormula (I) through (VII) and (XVI) through (XXIV) to an esterfunctional group: including, alkyl esters such as methyl, ethyl,isopropyl and n-butyl esters; aryl esters such as phenyl and indanylesters; double esters such as (acyloxy)alkyl or[(alkoxycarbonyl)oxy]methyl esters; and cyclic carbonates such as(oxodioxolyl)methyl esters. In another embodiment, the carboxylic acidmoiety may incorporate a carbamoylmethyl, aminoalkyl, or amidoalkylmoiety to provide carbamoylmethyl, aminoalkyl and amidoalkyl esters,respectively. In yet another embodiment, the carboxylic acid moiety canincorporate esters of acylglycerols and bis(acyl-amino)propan-2-ols. Ina further embodiment, the carboxylic acid moiety can incorporate amidegroups, including N-hydroxyamide, N-acylsulfonamides andN-acylsulfonylureas.

As used herein, a “metabolite” is a compound that, followingadministration to a subject, is converted within the body of the subjectto yield an active substance. Such conversion often involves hydrolysis,phosphorylation and/or oxidation/reduction processes, and may bemediated by any number of enzymes (e.g., esterases, phosphatases,cytochrome P450, and the like), as well by different environments withinthe body (e.g., changes in pH).

In one embodiment, compounds of Formula (I), as well as Formulas (II)through (XXII), as applicable, are modified to encompass metabolites ofthe parent compound. In another embodiment, compounds of Formula (I), aswell as Formulas (II) through (XXII), are modified to have the “A-ring”carboxylic acid of Formula (I) derivatized with carbohydrate or aminoacid compounds. In a further embodiment, the A-ring carboxylic acidmoiety is derivatized with glucuronic acid or the amino acid glycine togive compounds of Formulas (XXV) and (XXVI), respectively:

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of any one of Formulas (I) through(XIV) together with at least one pharmaceutically acceptable carrier,diluent, or excipient. For example, the active compound will usually bemixed with a carrier, or diluted by a carrier, or enclosed within acarrier which can be in the form of an ampoule, capsule, sachet, paper,or other container. When the active compound is mixed with a carrier, orwhen the carrier serves as a diluent, it can be solid, semi-solid, orliquid material that acts as a vehicle, excipient, or medium for theactive compound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

As used herein, the term “pharmaceutical composition” refers to acomposition containing one or more of the compounds described herein, ora pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope or salt thereof, formulated with a pharmaceutically acceptablecarrier, which can also include other additives, and manufactured orsold with the approval of a governmental regulatory agency as part of atherapeutic regimen for the treatment of disease in a mammal.Pharmaceutical compositions can be formulated, for example, for oraladministration in unit dosage form (e.g., a tablet, capsule, caplet,gelcap, or syrup); for topical administration (e.g., as a cream, gel,lotion, or ointment); for intravenous administration (e.g., as a sterilesolution free of particulate emboli and in a solvent system suitable forintravenous use); or in any other formulation described herein.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington: The Science and Practice of Pharmacy, 21^(st) Ed., Gennaro,Ed., Lippencott Williams & Wilkins (2005) and in The United StatesPharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

In some embodiments, the pharmaceutical composition comprising acompound of any one of Formulas (I) through (XIV) with at least onepharmaceutically acceptable carrier, diluent, or excipient furthercomprises a second therapeutic agent. In one embodiment, the secondtherapeutic agent is a liver disease therapeutic agent. In oneembodiment, the liver disease therapeutic agent is ursodeoxycholic acid(UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone,rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin,fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine,metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR)agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, athyroid hormone receptor beta (TRβ) agonist, or any combination thereof.

Examples of FXR agonists that may be used in the pharmaceuticalcompositions described herein include obeticholic acid, Turofexorateisopropyl (WAY-362450),3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole(GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101,altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl,fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor(GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023,AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480,INV-33, RDX023-02, or any combination thereof. In one embodiment, a FXRagonist is a bile acid or analog thereof (e.g., obeticholic acid,INT-767, INT-787, turofexorate isopropyl (WAY-362450), or BAR704) or anon-bile acid agonist (e.g., EDP-305, tropifexor, nidufexor, cilofexor,GW4064, Turofexorate isopropyl, fexaramine, PX20606 (PX-102), TERN-101,altenusin, silymarin, silybin, hedragonic acid, BAR502, EYP-001,RDX023-2, AGN-242266, HPG-1860, MET-409, EP-024297, M-480, or cafestol).

In one embodiment, a PPAR agonist is a PPAR-alpha agonist, a PPAR-gammaagonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPARalpha/delta dual agonist, a PPAR gamma/delta dual agonist, a PPARalpha/gamma/delta pan agonist, or any combination thereof.

Examples of PPAR alpha agonists that may be used in the pharmaceuticalcompositions described herein include fenofibrate, ciprofibrate,pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate,clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate,theofibrate, tocofibrate, and SRI 0171.

Examples of PPAR gamma agonists that may be used in the pharmaceuticalcompositions described herein include rosiglitazone, pioglitazone,deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405,CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, andALL-4.

Examples of PPAR delta agonists that may be used in the pharmaceuticalcompositions described herein include GW501516 (endurabol or({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (seladelpar or{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceticacid), GW0742([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy] acetic acid), L165041, HPP-593, and NCP-1046.

Examples of PPAR alpha/gamma agonists that may be used in thepharmaceutical compositions described herein include saroglitazar,aleglitazar, muraglitazar, tesaglitazar, and DSP-8658.

Examples of PPAR alpha/delta agonists that may be used in thepharmaceutical compositions described herein include elafibranor andT913659.

Examples of PPAR gamma/delta agonists that may be used in thepharmaceutical compositions described herein include a conjugatedlinoleic acid (CLA) and T3D-959.

Examples of PPAR alpha/gamma/delta agonists that may be used in thepharmaceutical compositions described herein include IVA337(lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148,GW9135, bezafibrate, lobeglitazone,2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoicacid (MHY2013), and CS038.

Examples of thyroid hormone receptor beta agonists that may be used inthe pharmaceutical compositions described herein include sobetirome,eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], andMB07811(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane).

As used herein, the term “pharmaceutically acceptable carrier” refers toany ingredient other than the disclosed compounds, or a pharmaceuticallyacceptable isomer, racemate, hydrate, solvate, isotope or salt thereof(e.g., a carrier capable of suspending or dissolving the activecompound) and having the properties of being nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspending or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substances,preserving agents, sweetening agents, or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal, or parenteral, includingintravenous, subcutaneous and/or intramuscular. In one embodiment, theroute of administration is oral. In another embodiment, the route ofadministration is topical.

Dosage forms can be administered once a day, or more than once a day,such as twice or thrice daily. Alternatively, dosage forms can beadministered less frequently than daily, such as every other day, orweekly, if found to be advisable by a prescribing physician or drug'sprescribing information. Dosing regimens include, for example, dosetitration to the extent necessary or useful for the indication to betreated, thus allowing the patient's body to adapt to the treatment, tominimize or avoid unwanted side effects associated with the treatment,and/or to maximize the therapeutic effect of the present compounds.Other dosage forms include delayed or controlled-release forms. Suitabledosage regimens and/or forms include those set out, for example, in thelatest edition of the Physicians' Desk Reference, incorporated herein byreference.

In one embodiment, the invention provides an oral pharmaceuticalcomposition comprising a compound of any one of Formulas (I) through(XXIV) together with at least one pharmaceutically acceptable oralcarrier, diluent, or excipient. In another embodiment, the inventionprovide a topical pharmaceutical composition comprising a compound ofany one of Formulas (I) through (XXIV) together with at least onepharmaceutically acceptable topical carrier, diluent, or excipient. Forexample, the oral pharmaceutical composition is provided to treatcholestatic pruritus, wherein the dosage regimen is, for example, once aday. In one embodiment, the topical pharmaceutical composition isprovided to treat atopic dermatitis.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

In certain embodiments, the invention provides a compound having thestructure of any one of Formulas (I) through (XXIV). Such compounds canbe synthesized using standard synthetic techniques known to thoseskilled in the art. For example, compounds of the present invention canbe synthesized using appropriately modified synthetic procedures setforth in the following Examples and Reaction Schemes. To this end,carboxylic acid isosteres, and their substitution in place of thecarboxylic acids disclosed herein, may also be accomplished usingstandard synthetic techniques known to those skilled in the art.

To this end, the reactions, processes, and synthetic methods describedherein are not limited to the specific conditions described in thefollowing experimental section, but rather are intended as a guide toone with suitable skill in this field. For example, reactions may becarried out in any suitable solvent, or other reagents to perform thetransformation(s) necessary. Generally, suitable solvents are protic oraprotic solvents which are substantially non-reactive with thereactants, the intermediates or products at the temperatures at whichthe reactions are carried out (i.e., temperatures which may range fromthe freezing to boiling temperatures). A given reaction may be carriedout in one solvent or a mixture of more than one solvent. Depending onthe particular reaction, suitable solvents for a particular work-upfollowing the reaction may be employed.

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art. The compounds and intermediates producedaccording to the methods of the invention may require purification.Purification of organic compounds is well known to a person skilled inthe art and there may be several ways of purifying the same compound. Insome cases, no purification may be necessary. In some cases, thecompounds may be purified by crystallization. In some cases, impuritiesmay be stirred out using a suitable solvent. In some cases, thecompounds may be purified by chromatography, particularly flash columnchromatography, using purpose-made or prepacked silica gel cartridgesand eluents such as gradients of solvents such as heptane, ether, ethylacetate, acetonitrile, ethanol and the like. In some cases, thecompounds may be purified by preparative HPLC using methods asdescribed.

Purification methods as described herein may provide compounds of thepresent invention which possess a sufficiently basic or acidicfunctionality in the form of a salt, such as, in the case of a compoundof the present invention which is sufficiently basic, a trifluoroacetateor formate salt, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt. A salt of this type caneither be transformed into its free base or free acid form,respectively, by various methods known to a person skilled in the art,or be used as salts in subsequent biological assays. It is to beunderstood that the specific form of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

Chemical names were generated using the ChemDraw naming software(Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases,generally accepted names of commercially available reagents were used inplace of names generated by the naming software.

EXAMPLES General Methods

¹H NMR (400 MHz) spectra were obtained in solution of deuteriochloroform(CDCl₃), deuteriomethanol (CD₃OD) or dimethyl sulfoxide—D6 (DMSO). HPLCretention times, purities and mass spectra (LCMS) were obtained usingone of the following methods:

Method 1: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 μm, 4.6×100 mm column, using H₂O with 0.1%formic acid as the mobile phase A, and MeCN with 0.1% formic acid as themobile phase B. An ESI detector in positive mode was used. The gradientwas 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, thenreturn to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.

Method 2: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 μm, 4.6×100 mm column, using H₂O with 0.1%formic acid as the mobile phase A, and MeCN with 0.1% formic acid as themobile phase B. An ESI detector in negative mode was used. The gradientwas 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, thenreturn to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.

Method 3: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 μm, 4.6×100 mm column, using H₂O with 0.1%formic acid as the mobile phase A, and MeCN with 0.1% formic acid as themobile phase B. An ESI detector in positive mode was used. The gradientwas 20-95% mobile phase B over 5 min then held at 95% for 3.8 mins, thenreturn to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min.

Method 4: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 μm, 4.6×100 mm column, using H₂O with 0.1%formic acid as the mobile phase A, and MeCN with 0.1% formic acid as themobile phase B. An ESI detector in negative mode was used. The gradientwas 10-95% mobile phase B over 12 min then held at 95% for 2 min, returnto 10% mobile phase B over 1 min. The flow rate was 1 mL/min.

Method 5: Shimadzu LCMS-2020 system equipped with a KinetiX EVO C182.1×30 mm, 5 μm column, using H₂O with 0.025% NH₃—H₂O as the mobilephase A, and MeCN as mobile phase B. The flow rate was 1.5 mL/min. AnESI mass detector in negative mode was used. The gradient was 0-60% Bover 0.8 min, then hold at 60% B for 0.4 min, then return to 0% B over0.01 min, and hold at 0% B for 0.34 min.

Method 6: Agilent 1200/G6110A System equipped with a Chromolith FlashRP-18e 25×2.0 mm column, using H₂O with 0.0375% TFA as mobile phase A,and MeCN with 0.01875% TFA as mobile phase B. An ESI mass detector setin positive mode was used. The gradient was 5-95% B over 0.8 min, holdat 95% B for 0.4 min, then return to 5% B over 0.01 min, and hold at 5%B for 0.29 min.

Method 7: Shimadzu LCMS-2020 system equipped with a KinetiX EVO C182.1×30 mm, 5 μm column, using H₂O with 0.025% NH₃ as the mobile phase A,and MeCN as mobile phase B. The flow rate was 1.5 mL/min. An ESI massdetector in negative mode was used. The gradient was 5-95% B over 0.8min, hold at 95% B for 0.4 min, then return to 5% B over 0.01 min, andhold at 5% B for 0.34 min.

Method 8: Agilent 1200/G6110A System equipped with an ACE Excel C18,2.1×30 mm, 5 μm column, using H₂O with 0.025% NH₃ as mobile phase A, andMeCN as mobile phase B. An ESI mass detector set in negative mode wasused. The gradient was 10-80% B over 1.2 min, hold at 80% B for 0.4 min,then return to 5% B over 0.01 min, and hold at 5% B for 0.39 min.

Method 9: Agilent 1100 System equipped with an Agilent Eclipse XDB-C18,3.5 μm, 4.6×150 mm column, using H₂O with 0.1% trifluoroacetic acid asthe mobile phase A, and methanol with 0.1% trifluoroacetic acid as themobile phase B. The gradient was 5-95% mobile phase B over 12 min thenheld at 95% mobile phase B for 3 min, then return to 5% mobile phase Bfor 1 min. The flow rate was 1 mL/min.

Method 10: Shimadzu SCL-10A system equipped with Agilent EclipseXDB-C18, 3.5 μm, 4.6×150 mm column and PE Sciex API 150 EX, using H₂Owith 0.1% trifluoroacetic acid as the mobile phase A, and methanol with0.1% trifluoroacetic acid as the mobile phase B. The gradient was 5-95%mobile phase B over 12 min then held at 95% mobile phase B for 3 min,then return to 5% mobile phase B for 1 min. The flow rate was 1 mL/min.

Method 11: Shimadzu SCL-10A system equipped with Agilent EclipseXDB-C18, 3.5 μm, 4.6×150 mm column and PE Sciex API 150 EX, using H₂Owith 0.1% trifluoroacetic acid as the mobile phase A, and methanol with0.1% trifluoroacetic acid as the mobile phase B. The gradient was 50-95%mobile phase B over 4 min then held at 95% mobile phase B for 4 min,then return to 50% mobile phase B for 0.1 min. The flow rate was 1mL/min.

Method 12: Waters Acquity system equipped with an Acquity UPLC BEH C181.7 μm, 2.1×50 mm column, using H2O with 0.1% ammonium formate adjustedto pH 3.8 with formic acid as the mobile phase A, and acetonitrile asthe mobile phase B. The gradient was 5-100% over 9 minutes then held at100% mobile phase B for 1 minute. The flow rate was 0.7 mL/min.

Method 13: Waters Acquity system equipped with an EVO C18 (5 μm, 3.0×50mm) using a low pH buffer gradient of 5% to 100% of MeCN in H₂O (0.1%HCOOH) over 2.5 min at 2.2 mL/min, and holding at 100% for a total timeof 3.5 min.

The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and tolueneused in the procedures were from Aldrich Sure-Seal bottles kept undernitrogen (N₂). All reactions were stirred magnetically, and temperaturesare external reaction temperatures. Chromatographies were typicallycarried out using a Combiflash Rf flash purification system (TeledyneIsco) equipped with Redisep (Teledyne Isco) Rf Gold Normal-Phase silicagel (SiO₂) columns or by using a similar system.

Preparative HPLC purifications were typically performed using one of thefollowing systems: 1) Waters System equipped with a Waters 2489 uv/visdetector, an Aquity QDA detector, a Waters xBridge Prep C18 5 μm OBD,30×1560 mm column, and eluting with various gradients of H₂O/MeCN (0.1%formic acid) at a 30 mL/min flow rate, or 2) column: Phenomenex SynergiC18 150×30 mm-4 μm; mobile phase: [H₂O (0.225% formic acid)-MeCN]; B %:55%-85%, 12 min) and were typically concentrated using a Genevac EZ-2.

The following additional abbreviations are used: ethyl acetate (EA),triethylamine (TEA), dimethyl sulfoxide (DMSO), silica gel (Si₂),azobisisobutyronitrile (AIBN), diisobutylaluminium hydride (DIBAL),trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP),diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO),1,1′-bis(diphenylphosphino)ferrocene (dppf or DPPF), tetrahydrofuran(THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO),hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU),hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM),N-Bromosuccinimide (NBS), diisopropylethyl amine (DIPEA), diethylazodicarboxylate (DEAD),2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC),isopropanol (IPA), dimethylformamide (DMF), dimethyl acetamide (DMA),acetonitrile (MeCN or ACN), 1,1′-thiocarbonyldiimidazole (TCDI),petroleum ether (PE), not determined (ND), retention time (RT),molecular weight (MW), room temperature (rt), hour (h), and notapplicable (N/A).

Example 1 Synthesis of Compound 1-0, Compound 1-16 and OtherRepresentative Compounds

Step 1-1. Synthesis of methyl3-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0)

To a stirring solution of methyl 3-(bromomethyl)benzoate (150 mg, 655μmol) in MeCN (3 mL) were added 2-methyl-4-(trifluoromethyl)phenol (115mg, 655 μmol) and K₂CO₃ (118 mg, 0.85 mmol). The reaction mixture washeated at 60° C. for 3 h then cooled to room temperature and dilutedwith H₂O (3 mL). The aqueous layer was extracted with Et₂O (2×6 mL) andEA (1×6 mL) and the combined organic layers were dried (Na₂SO₄),filtered, concentrated and purified by SiO₂ chromatography (EA/hexanes)to afford 203 μmg (77.4%) of methyl3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (Compound 1-0)as a white solid. LCMS-ESI (m/z) calculated for C₁₇H₁₅F₃O₃: 324.3; found346.1 [M+Na]⁺, t_(R)=6.68 min (Method 1).

The compounds listed in Table 1A were made using the procedures ofScheme 1.

TABLE 1A Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

1-1  12.02 344.71 367.0 [M + Na]⁺ 3

1-2  12.03 344.71 345.1 [M + H]⁺ 3

1-3  10.34 301.73 302.1 [M + H]⁺ 3

1-4  12.02 311.16 313.1 [M + H]⁺ 3

1-5  10.65 260.26 261.2 [M + H]⁺ 3

1-6  11.63 326.27 327.1 [M + H]⁺ 3

1-7   8.56 327.38 328.2 [M + H]⁺ 3

1-8   9.48 299.34 300.1 [M + H]⁺ 3

1-9   9.98 313.13 313.1 [M − H]⁺ 4

1-10  10.75 345.70 346.1 [M + H]⁺ 3

1-11  10.68 345.70 346.1 [M + H]⁺ 3

1-12   9.97 293.32 294.2 [M + H]⁺ 3

1-13  10.39 291.73 292.1 [M + H]⁺ 3

1-14  11.64 315.97 317.0 [M + H]⁺ 3

1-15  10.32 300.99 302.1 [M + H]⁺ 3

1-117 10.36 362.7  361   [M − H]⁺ 4

Step 1-2. Synthesis of3-((2-methyl-4-(trifluoromethyl)phenox)methyl)benzoic acid (Compound1-16)

To a stirring solution of methyl3-((2-methyl-4-(trifluoromethyl)-phenoxy)methyl)benzoate (Compound 1-0)(206 mg, 0.635 mmol) in THE (3 mL) was added 1M NaOH (3 mL, 3.18 mmol).The reaction mixture was heated at 60° C. overnight, the volatiles wereremoved in vacuo, and the resulting aqueous layer was acidified with 3MHCl. The resulting solution was extracted with EA and Et₂, dried(Na₂SO₄), filtered and concentrated to give a crude solid that waspurified by reversed phase SiO₂ chromatography to afford 155 mg (79) of3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (Compound1-16) as a white solid. LCMS-ESI (m/z) calculated for C₁₆H₁₃F₃O₃: 310.2;found 333.1 [M+Na]⁺, t_(R)=10.4 min. (Method 3).

The compounds listed in Table 1B were made using the procedures ofScheme 1.

TABLE 1B Purity Cpd RT Oserved Purity Structure No. (min) MW m/z IonMethod

1-16  10.39 310.27 333.1, [M + Na]⁺ 3

1-17   0.827 278.31 277   [M − H]⁺ 5

1-18  10.15 297.13 299.1 [M + H]⁺ 3

1-19   9.90 297.13 296.0 [M − H]⁺ 4

1-20  ND 292.72 ND N/A N/A

1-21   9.38 262.69 263.1 [M + H]⁺ 3

1-22   9.04 262.69 263.1 [M + H]⁺ 3

1-23   9.43 280.68 281.1 [M + H]⁺ 3

1-24   9.29 280.68 281.0 [M + H]⁺ 3

1-25   9.70 297.13 296.0 [M − H]⁺ 4

1-26   8.98 287.09 311.0 [M + Na]⁺ 3

1-27   0.95 327.16 329.1 [M + H]⁺ 6

1-28  10.32 330.69 353.1 [M + Na]⁺ 3

1-29  10.29 330.69 353.1 [M + Na]⁺ 3

1-30   8.61 279.30 280.2 [M + H]⁺ 3

1-31   9.51 331.68 332.1 [M + H]⁺ 3

1-32   0.932 327.16 327.1 [M + H]⁺ 6

1-33  10.14 268.31 269.2 [M + H]⁺ 3

1-34   7.86 253.26 254.2 [M + H]⁺ 3

1-35   8.59 287.70 288.1 [M + H]⁺ 3

1-36   8.04 263.68 264.1 [M + H]⁺ 3

1-37   7.97 258.27 259.2 [M + H]⁺ 3

1-38   8.28 258.27 259.1 [M + H]⁺ 3

1-39   8.51 258.27 259.2 [M + H]⁺ 3

1-40   8.47 246.24 247.2 [M + H]⁺ 3

1-41   9.70 296.25 319.1 [M + Na]⁺ 3

1-42  10.14 268.31 269.2 [M + H]⁺ 3

1-43   9.66 303.15 305.0 [M + H]⁺ 3

1-44   0.702 331.57 328.8 [M − H]⁺ 7

1-45   0.629 272.30 271.0 [M − H]⁺ 7

1-46   9.84 268.31 269.2 [M + H]⁺ 3

1-47   9.89 312.24 313.2 [M + H]⁺ 3

1-48   9.53 308.24 307.0 [M − H]⁺ 3

1-49   0.707 278.31 277.0 [M − H]⁺ 7

1-50   0.720 311.16 308.9 [M − H]⁺ 7

1-51   0.938 318.37 341.0 [M + Na]⁺ 6

1-52   0.904 320.34 321.1 [M + H]⁺ 6

1-53   0.915 290.74 291.1 [M + H]⁺ 6

1-54   7.50 270.28 271.2 [M + H]⁺ 3

1-55  10.29 348.68 349.1 [M + H]⁺ 3

1-56   9.40 331.68 332.1 [M + H]⁺ 3

1-57   8.97 277.70 278.2 [M + H]⁺ 3

1-58   9.84 296.30 297.2 [M + H]⁺ 3

1-59   0.813 280.68 278.9 [M − H]⁺ 5

1-60   0.823 274.29 272.9 [M − H]⁺ 5

1-61   9.73 308.24 307.0 [M − H]⁺ 4

1-62  10.35 348.68 348.1 [M + H]⁺ 3

1-63  10.18 294.71 295.2 [M + H]⁺ 3

1-64   9.71 314.24 337.1 [M + Na]⁺ 3

1-65  10.67 348.68 346.1 [M − H]⁺ 4

1-66   8.268 299.10 299.1 [M + H]⁺ 3

1-67   9.68 326.27 327.1 [M + H]⁺ 3

1-68   0.796 321.26 319.9 [M − H]⁺ 5

1-69   0.899 322.34 321.0 [M − H]⁺ 5

1-70   0.757 287.70 285.9 [M − H]⁺ 5

1-71  0.8 278.25 276.9 [M − H]⁺ 5

1-72   0.683 276.72 274.9 [M − H]⁺ 5

1-73  10.14 364.2  363.0 [M − H]⁺ 4

1-74   0.703 282.3  280.9 [M − H]⁺ 5

1-75   0.766 280.7  278.9 [M − H]⁺ 5

1-76   0.739 287.7  285.9 [M − H]⁺ 5

1-77   0.84 260.3  261.1 [M − H]⁺ 6

1-78   0.727 331.57 328.8 [M − H]⁺ 7

1-79   0.717 330.7  328.9 [M − H]⁺ 7

1-80   0.68 293.3  292   [M − H]⁺ 7

1-81  14.24 304.4  327.1 [M + Na]⁺ 10 

1-82  11.26 365.13 363.0 [M − H]⁺ 4

1-83  10.61 365.13 365.0 [M − H]⁺ 4

1-84   8.67 272.30 273.2 [M + H]⁺ 3

1-85  10.16 348.68 349.1 [M + H]⁺ 3

1-86  10.47 270.33 271.2 [M + H]⁺ 3

1-87   0.754 296.32 294.5 [M − H]⁺ 5

1-88   0.915 298.4  297   [M − H]⁺ 5

1-89   0.78 260.3  259   [M − H]⁺ 5

1-90   0.751 287.70 285.9 [M − H]⁺ 5

1-91   0.817 314.24 312.9 [M − H]⁺ 5

1-92   0.773 292.72 290.9 [M − H]⁺ 5

1-94   0.774 260.26 259   [M − H]⁺ 5

1-95   0.824 276.72 274.9 [M − H]⁺ 5

1-96   0.752 294.25 292.9 [M − H]⁺ 5

1-97  0.785 284.33 282.9 [M − H]⁺ 5

1-98   0.607 279.30 280.1 [M + H]⁺ 6

1-99   1.13 267.28 266.1 [M − H]⁺ 5

1-100  8.80 278.25 301.1 [M + Na]⁺ 3

1-101 10.33 328.26 351.1 [M + Na]⁺ 3

1-102  8.28 297.23 298.2 [M + H]⁺ 3

1-103 10.46 346.69 369.1 [M + Na]⁺ 3

1-108  0.762 298.38 297.0 [M − H]⁺ 7

1-109  0.749 307.14 305.0 [M − H]⁺ 8

1-110  0.574 307.14 306.8 [M − H]⁺ 7

1-112  9.88 314.24 337.1 [M + Na]⁺ 3

1-113 ND 296.00 ND N/A N/A

1-114 10.72 296.00 297.1 [M + H]⁺ 3

1-115  9.12 298.12 300.1 [M + H]⁺ 3

1-116  8.27 299.11 299.1 [M + H]⁺ 3

1-118  10.362 330.69 329   [M − H]⁺ 4

1-119  10.362 330.69 329   [M − H]⁺ 4

1-120 10.43 375.14 399.0 [M + Na]⁺ 3

1-121  10.872 364.68 363.0 [M − H]⁺ 4

1-122  10.385 302.75 301.2 [M − H]⁺ 4

1-123  11.165 349.56 348.0 [M − H]⁺ 4

1-124  10.773 349.56 347.0 [M − H]⁺ 4

1-125  9.637 347.67 348.1 [M + H]⁺ 3

1-126  8.279 304.73 303   [M − H]⁺ 4

1-127  9.325 311.26 312.2 [M + H]⁺ 4

1-128  8.906 268.27 267.2 [M − H]⁺ 4

1-129  9.54 347.67 348.1 [M + H]⁺ 3

1-130  10.488 312.75 311   [M − H]⁺ 4

1-131  8.828 268.27 267.2 [M − H]⁺ 4

1-132  10.581 346.69 345   [M − H]⁺ 4

1-133  9.625 331.68 332.1 [M − H]⁺ 3

1-134  9.469 284.33 283   [M − H]⁺ 4

1-135  8.881 294.25 293.2 [M − H]⁺ 4

1-136  10.155 366.67 366   [M + H]⁺ 3

1-137  7.673 331.68 332.1 [M + H]⁺ 3

1-138  4.97 310.27  309.07 [M − H]⁺ 12 

1-139  5.09 326.27  325.07 [M − H]⁺ 12 

1-140 13.65 296.25 297.4 [M + H]⁺ 10 

1-141 13.09 296.25 295   [M − H]⁺ 10 

1-142  0.704 341.59 340.8 [M − H]⁺ 7

1-143  0.719 311.16 308.9 [M − H]⁺ 7

1-144  0.733 284.36 283   [M − H]⁺ 7

1-145  0.387 267.28 265.9 [M − H]⁺ 7

1-146  1.244 270.33 269.1 [M − H]⁺ 5

1-147  0.722 308.33 — — 7

1-148  1.234 315.12 313   [M − H]⁺ 5

1-149  1.238 315.12 313   [M − H]⁺ 5

1-150  0.688 267.28 265.9 [M − H]⁺ 5

1-151  1.117 296.32 295.1 [M − H]⁺ 5

1-152  0.615 285.30 285.9 [M − H]⁺ 7

1-153  0.748 305.69 303.9 [M − H]⁺ 5

1-154  0.719 298.29 296.9 [M − H]⁺ 5

Example 2 Synthesis of Compound 2-1 and Other Representative Compounds

Step 2-1. Synthesis of methyl3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A)

To a stirring solution of methyl 3-chloro-5-hydroxybenzoate (100 mg,0.50 mmol) in DCM (5 mL) were added triphenylphosphine (131 mg, 0.50mmol) and DEAD (108.7 μL, 0.60 mmol). The reaction mixture was purgedwith N₂ (3×) and stirred at 10° C. for 16 h (under an atmosphere of N₂)then concentrated and purified by flash SiO₂ chromatography(EA/petroleum ether) to afford 150 mg (87.0%) of methyl3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A) as a pinksolid. TLC (10% EA/petroleum ether): R_(f)=0.50. ¹H NMR (400 MHz,CDCl₃-d) δ 7.99 (d, J=1.8 Hz, 2H), 7.70-7.66 (m, 1H), 7.42 (d, J=2.6 Hz,1H), 7.34 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.14 (s, 2H), 3.95(s, 3H).

Step 2-2. Synthesis of 3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoicacid (Compound 2-1)

To a stirring solution of methyl3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 2-A) (100 mg, 0.29mmol) in MeOH (1 mL) and THE (1 mL) was added 2M NaOH (0.43 mL, 0.87mmol). The reaction mixture was heated at 30° C. for 1 h and thenconcentrated in vacuo. The resulting residue was purified by reversedphase HPLC to afford 12.6 mg (13%) of3-chloro-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 2-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₄H₉Cl₃O₃: 331.5; found328.8 [M−H]⁺, t_(R)=0.72 min. ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (s, 1H),7.86 (s, 1H), 7.77 (s, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.40 (dd, J=2.6, 8.8Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 5.31 (s, 2H).

The compounds listed in Table 2 were made using the procedures of Scheme2.

TABLE 2 Purity Cpd RT Oserved Purity Structure No. (min) MW m/z IonMethod

2-1 0.724 331.57 328.8 [M − H]⁺ 4

2-2 10.43 360.71 383.1 [M + Na]⁺ 3

2-3 11.38 409.58 433.0 [M + Na]⁺ 3

2-4  0.73  346.5  346   [M − H]⁺ 7

Example 3 Synthesis of Compound 3-1, Compound 3-2 and OtherRepresentative Compounds

Step 3-1. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile(INT 3-A)

To a stirring solution of 3-(bromomethyl)benzonitrile (500 mg, 2.55mmol) in DMF (8 mL) were added 2-chloro-4-methylphenol (360 mg, 2.5mmol) and Na₂CO₃ (0.81 g, 7.65 mmol). The reaction mixture was stirredat rt overnight then quenched with 150 mL of H₂O. The resultingprecipitate was collected, washed with H₂O (2×20 mL) and dried to afford600 mg (91.3%) of 3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT3-A). LCMS-ESI (m/z) calculated for C₁₈H₁₂ClNO: 257.7; found 258.0[M+H]⁺, t_(R)=5.43 min. (Method 11).

The compound listed in Table 3A was made using the procedures of Scheme3, Step 3-1 using 3-(bromomethyl)benzonitrile and 2,4-dichlorophenol.

TABLE 3A Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

3-1 11.49 278.13 277 [M − H]⁺ 4

Step 3-2. Synthesis of 3-((2-chloro-4-methylphenoxy)methyl)benzoic acid(Compound 3-2)

To a stirring solution of3-((2-chloro-4-methylphenoxy)methyl)benzonitrile (INT 3-A) (300 mg, 0.12mmol) in MeOH (5 mL) was added a solution of NaOH (375 mg, 9.4 mmol) inH₂O (8 mL). The reaction vessel was sealed and stirred at 90° C.overnight then cooled to room temperature and concentrated to remove theMeOH. The aqueous layer was washed with EA and acidified with 4N HCl.The resulting precipitate was collected to provide 210 mg (65%) of3-((2-chloro-4-methylphenoxy)methyl)benzoic acid (Compound 3-2).LCMS-ESI (m/z) calculated for C₁₅H₁₃Cl₁O₃: 276.7; found 277.3 [M+H]⁺,t_(R)=14.01 min. ¹H NMR (400 MHz, CDCl₃): 8.19 (s, 1H), 8.06 (d, J=8 Hz,1H), 7.77 (d, J=8 Hz, 1H), 7.53 (t, J=8 Hz, 1H), 7.22 (s, 1H), 6.99 (d,J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 5.18 (s, 2H), 2.27 (s, 3H).

The compounds listed in Table 3B were made using the procedures ofScheme 3, Step 3-2.

TABLE 3B Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

3-2 14.01 276.72 277.3 [M + H]⁺  3

3-3 11.49 278.13 305.1 [M + H]⁺  3

3-4 11.49 278.13 297.5 [M + H]⁺  3

3-5 11.49 278.13 275   [M − H]⁺  4

3-6 11.49 278.13 297   [M − H]⁺  4

3-7 11.49 278.13 257.5 [M + H]⁺ 10

3-8 11.49 278.13 311.3 [M + H]⁺ 10

3-9 11.49 278.13 297.6 [M + H]⁺ 10

Example 4 Synthesis of Compound 4-1 and Other Representative Compounds

Step 4-1. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT-4A)

To a stirring solution of methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.95mmol) in CCl₄ (5 mL) were added NBS (1.06 g, 5.95 mmol) and AIBN (19.6mg, 119 mmol). After stirring at 100° C. for 2 h, the reaction mixturewas concentrated, and the resulting residue was purified by SiO₂chromatography to provide 858 mg (58%) of methyl3-(bromomethyl)-2-fluorobenzoate (INT-4A) as a white solid. TLC (10%EA/petroleum ether): R_(f)=0.50. LCMS-ESI (m/z) calculated forC₉H₈BrFO₂: 245.97; found 247.0 [M+H]⁺, t_(R)=0.86 min (Method 6).

Step 4-2. Synthesis of methyl3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT 4-B)

To a stirring solution of methyl 3-(bromomethyl)-2-fluorobenzoate(INT-4A) (500 mg, 2.02 mmol) in MeCN (2 mL) were added K₂CO₃ (559.4 mg,4.05 mmol) and 2,4-dichlorophenol (329.9 mg, 2.02 mmol). After stirringat 50° C. for 16 h, the reaction mixture was concentrated and theresulting residue was purified by flash SiO₂ chromatography to provide537 mg (81%) of methyl 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate(INT 4-B) as a white solid. TLC (10% EA/petroleum ether): R_(f)=0.45.LCMS-ESI (m/z) calculated for C₁₅H₁₁Cl₂BrFO₃: 328.01; found 329.1[M+H]⁺, t_(R)=1.03 min (Method 6).

Step 4-3. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoicacid (Compound 4-1)

To a stirring solution of methyl3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoate (INT 4-B) (100 mg,0.303 mmol) in MeOH (1 mL) and THE (1 mL) was added a solution of 2 MNaOH (455.7 μL, 0.9 mmol). After stirring at 10° C. for 16 h, thereaction mixture was concentrated and the resulting residue was purifiedby prep HPLC to provide 6.4 mg (7%) of3-((2,4-dichlorophenoxy)methyl)-2-fluorobenzoic acid (Compound 4-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₄H₉Cl₂FO₃: 313.99; found312.9 [M−H]⁺, t_(R)=0.663 min (Method 7). ¹H NMR (400 MHz, DMSO-d6) δ7.84 (t, J=6.7 Hz, 1H), 7.75 (br t, J=7.0 Hz, 1H), 7.60 (d, J=2.4 Hz,1H), 7.42-7.30 (m, 3H), 5.28 (s, 2H).

Synthesis of Compound 1-55

Step 4-4. Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate (INT 4-C)

To a stirring solution of methyl 2-fluoro-3-methylbenzoate (1.0 g, 5.9mmol) in CCl₄ (20 mL) were added NBS (1.2 g, 6.5 mmol) and AIBN (98 mg,0.59 mmol). The reaction mixture was heated to reflux for 3 h, thencooled to rt and concentrated in vacuo to afford crude product. Thecrude product was purified by SiO₂ chromatography (EA/hexanes) to afford399 mg (27%) of methyl 3-(bromomethyl)-2-fluorobenzoate (INT 4-C) as awhite solid. LCMS-ESI (m/z) not observed, t_(R)=5.05 min. (Method 7minute).

Step 4-5. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT4-D)

To a stirring solution of INT 4-C (449 mg, 1.82 mmol) in MeCN (4 mL)were added 2-chloro-4-(trifluoromethyl)phenol (357 mg, 1.82 mmol) andK₂CO₃ (327 mg, 2.36 mmol). After heating for 18 h at 60° C., thereaction mixture was cooled to rt and diluted with H₂O (3 mL). Theaqueous layer was extracted with Et₂O (2×6 mL) and by EA (6 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentratedin vacuo to afford a crude white solid that was purified by SiO₂chromatography (EA/hexanes) to afford 551.6 mg (83.7%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT4-D) as a white solid. LCMS-ESI (m/z) calculated for C₁₆H₁₁ClF₄O₃:362.7; found 363.1 [M+H]⁺, (Method 7 minute).

Step 4-6. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(1-55)

To a stirring solution of INT 4-D (551 mg, 1.52 mmol) in THE (8 mL) wasadded 1M NaOH (7.6 mL, 7.60 mmol). The reaction mixture was heated at60° C. overnight then concentrated in vacuo, diluted with 3M HCl,extracted with EA and Et₂O, dried (Na₂SO₄), filtered and concentrated invacuo. The resulting white solid was dissolved in MeCN (5 mL) and H₂O (5mL) and lyophilized to afford 460.5 mg (86.9%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(Compound 1-55) as a white solid. LCMS-ESI (m/z) calculated forC₁₅H₉ClF₄O₃: 348.68; found 349.1 [M+H]⁺, t_(R)=10.28 min. (15 minpurity). ¹H NMR (500 MHz, DMSO-d6) δ 13.36 (br s, 1H), 7.92-7.87 (m,2H), 7.83-7.80 (m, 1H), 7.73 (dd, J=8.5, 2.0 Hz, 1H), 7.51 (d, J=8.5 Hz,1H), 7.36 (app t, J=7.5 Hz, 1H), 5.40 (s, 2H).

Synthesis of Compound 1-65

Step 4-7. Synthesis of methyl 3-fluoro-5-methylbenzoate (INT 4-E)

A solution of 3-fluoro-5-methyl-benzoic acid (5 g, 32.4 mmol) and H₂SO₄(15.91 g, 162.2 mmol, 8.65 mL) in MeOH (30 mL) was stirred at 70° C. for12 h. The reaction mixture was poured into H₂O (100 mL) and extractedinto EA. The combined organic phases were dried and concentrated to givea residue that was purified by SIO₂ chromatography (PE/EA) to provide4.5 g (82.5%) of methyl 3-fluoro-5-methyl-benzoate (INT 4-E) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.40 (s, 3H) 3.92 (s, 3H) 7.08 (br d,J=9.26 Hz, 1H) 7.51 (br d, J=9.13 Hz, 1H) 7.65 (s, 1H).

Step 4-8. Synthesis of methyl 3-(bromomethyl)-5-fluorobenzoate (INT 4-F)

A solution of methyl INT 4-E (4.5 g, 26.76 mmol), NBS (5.24 g, 29.44mmol) and AIBN (219.71 mg, 1.34 mmol) in CCl₄ (50 mL) was stirred at 70°C. for 12 hr. The reaction was concentrated and purified by SiO₂chromatography (PE/EA) to provide 4.9 g (74%) of crude methyl3-(bromomethyl)-5-fluoro-benzoate (INT 4-F) as a yellow oil. TLC (10:1petroleum ether:EA): R_(f)=0.70. 1H NMR (400 MHz, CDCl₃) δ ppm 7.86 (t,J=1.41 Hz, 1H) 7.64-7.67 (m, 1H) 7.31 (dt, J=8.71, 2.06 Hz, 1H), 4.48(s, 2H) 3.94 (s, 3H).

Step 4-9. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoate (INT4-G)

A mixture of INT 4-F (3 g, 12.1 mmol),2-chloro-4-(trifluoromethyl)phenol (3.58 g, 18.2 mmol) and K₂CO₃ (5.03g, 36.4 mmol) in MeCN (50 mL) was stirred at 30° C. for 12 hr. Thereaction mixture was filtered and concentrated to give a residue thatwas purified by SiO₂ chromatography (PE/EA) to provide 2.4 g (55%) ofmethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoate(INT 4-G) as a white solid. TLC (5:1 petroleum ether:EA): R_(f)=0.60.

Step 4-10. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoic acid(1-65)

A mixture of INT 4-G (2.4 g, 6.6 mmol) and NaOH (794 mg, 19.9 mmol) inTHE (1 mL) and H₂O (0.5 mL) was stirred at 30° C. for 2 hr. The reactionmixture was acidified with 1N HCl and extracted with EA. The combinedorganic layers were dried (Na₂SO₄) and concentrated to provide a residuethat was dissolved in PE/EA and filtered. The filter cake was dilutedwith MeCN/H₂O and lyophilized to provide 1.91 g (82%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-fluorobenzoic acid(Compound 1-56) as a white solid. LCMS-ESI (m/z) calculated forC₁₅H₉ClF₄O₃: 348.6; found 347.0 [M−H]⁺, t_(R)=0.958 min. (Method 8). ¹HNMR (400 MHz, CDCl₃-d) δ ppm 7.99 (s, 1H) 7.77 (br d, J=8.19 Hz, 1H)7.70 (d, J=1.96 Hz, 1H) 7.51 (br d, J=8.68 Hz, 2H) 7.03 (d, J=8.56 Hz,1H) 5.26 (s, 2H).

Synthesis of Compound 1-85

Step 4-11. Synthesis of methyl 2-fluoro-5-methylbenzoate (INT 4-H)

To a solution of 2-fluoro-5-methyl-benzoic acid (10 g, 64.9 mmol) inMeOH (200 mL) was added thionyl chloride (23.53 mL, 324.4 mmol) dropwiseat 25° C. After 0.5 h at 25° C., the mixture was concentrated andpurified by SiO₂ chromatography (PE/EA) to provide 10.6 g (97%) ofmethyl 2-fluoro-5-methylbenzoate (INT 4-H) as a colorless oil. TLC (1:1petroleum ether:EA): R_(f)=0.90.

Step 4-12. Synthesis of methyl 5-(bromomethyl)-2-fluorobenzoate (INT4-I)

Into a solution of INT 4-H (8 g, 47.6 mmol), in CHCl₃ (200 mL) wereadded NBS (10.16 g, 57.1 mmol) and AIBN (781.2 mg, 4.76 mmol). After 12h at 70° C., the reaction was diluted with H₂O (200 mL) and extractedinto EA (3×100 mL). The combined organic layers were dried (Na₂SO₄),concentrated and purified by SiO₂ chromatography (PE/EA) to provide 10.6g (97%) of methyl 5-(bromomethyl)-2-fluorobenzoate (INT 4-I) as a whitesolid that was contaminated with a second, unidentified product. TLC(10:1 petroleum ether:EA): R_(f)=0.4, 0.35. LCMS-ESI (m/z) calculatedfor C₉H₈BrFO₂: 247.06; found 248.8 [M−H]⁺, t_(R)=0.702 min. ¹H NMR (400MHz, CDCl₃-d) δ 8.01-7.94 (m, 1H), 7.62-7.52 (m, 1H), 7.17-7.10 (m, 1H),4.49 (s, 2H), 3.95 (s, 3H).

Step 4-13. Synthesis of methyl5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT4-J)

To a solution of INT 4-I (4 g, 16.19 mmol) and2-chloro-4-(trifluoromethyl)phenol (3.18 g, 16.19 mmol) in MeCN (30 mL)was added K₂CO₃ (6.71 g, 48.57 mmol). After 2 h at 50° C., the reactionmixture was filtered, concentrated, and purified by SiO₂ chromatography(PE) to provide 1.7 g (29%) of methyl5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate (INT4-J) as a white solid. TLC (10:1 petroleum ether:EA): R_(f)=0.40.LCMS-ESI (m/z) calculated for C₆H₁₁ClF₄O₃: 362.7; found 363.0 [M−H]+,t_(R)=1.07 min (Method 6). ¹H NMR (400 MHz, CDCl₃-d) δ 8.05 (dd, J=2.3,6.7 Hz, 1H), 7.72-7.63 (m, 2H), 7.55-7.45 (m, 1H), 7.26-7.15 (m, 1H),7.04 (d, J=8.6 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H).

Step 4-14. Synthesis of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(1-85)

To a solution of INT 4-J (1.7 g, 4.63 mmol) in H₂O (10 mL), THE (10 mL)and MeOH (5 mL) was added LiOH.H₂O (582.33 mg, 13.88 mmol). After 2 h at25° C., H₂O (30 μL) was added into the reaction mixture and the organicsolvent was removed by reduced pressure to provide 1.57 g (97%) of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(Compound 1-85) as a white solid. LCMS-ESI (m/z) calculated forC₁₅H₉ClF₄O₃: 348.68; found 349.0 [M−H]⁺, t_(R)=0.925 min. (Method 6). ¹HNMR (400 MHz, DMSO-d6) δ 7.96-7.90 (m, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.72(dd, J=1.7, 8.7 Hz, 1H), 7.66 (dt, J=2.3, 5.3 Hz, 1H), 7.44 (d, J=8.6Hz, 1H), 7.36-7.28 (m, 1H), 5.34 (s, 2H).

Synthesis of Compound 1-101

Step 4-15. Synthesis of4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane(INT 4-K)

Into a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (7.3 g,30.5 mmol) in dioxane (100 mL) were added AcOK (11.99 g, 122.16 mmol, 4eq), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (15.51g, 61.1 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (2.49 g, 3.05 mmol). After stirringfor 12 h at 100° C. under N₂, The mixture was filtered and the filtratewas concentrated to give a crude product that was purified by SiO₂chromatography (PE) to provide 6.3 g (72%) of4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane(INT 4-K) as a yellow oil. TLC (PE): R_(f)=0.90. ¹H NMR (400 MHz,CDCl₃-d) δ 7.93-7.84 (m, 1H), 7.46-7.39 (m, 2H), 2.61 (s, 3H), 1.38 (s,13H).

Step 4-16. Synthesis of 2-methyl-4-(trifluoromethyl)phenol (INT 4-L)

To a solution of INT 4-K (5.8 g, 20.27 mmol) in EtOH (40 mL) and H2O (20mL) was added m-CPBA (6.17 g, 30.41 mmol, 85% purity). After stirringfor 12 h at 25° C. the mixture was poured into saturated Na2SO₃ (100 mL)and concentrated to remove volatiles. The resulting solution was dilutedwith H₂O (50 mL) and extracted with EA (3×80 mL). The combined organiclayers were washed with saturated NaHCO₃ solution (2×50 mL) and brine(100 mL×2), then dried (Na₂SO₄), concentrated and purified by SiO₂chromatography to provide 2.5 g (70%) of2-methyl-4-(trifluoromethyl)phenol (INT 4-L) as a colorless oil. TLC(5:1 PE:EA): R_(f)=0.50. ¹H NMR (400 MHz, CDCl₃-d) δ 7.45-7.39 (m, 1H),7.38-7.32 (m, 1H), 6.90-6.79 (m, 1H), 5.87-5.77 (m, 1H), 2.31 (s, 3H).

Step 4-17. Synthesis of methyl2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)-methyl)benzoate (INT4-M)

To a solution of INT 4-C (2.8 g, 11.33 mmol) and INT 4-L (2.4 g, 13.6mmol) in MeCN (30 mL) was added K₂CO₃ (2.04 g, 14.7 mmol). After 12 h at60° C., the reaction mixture was filtered, concentrated, and purified bySiO₂ chromatography (EA/PE) to provide 3.0 g (77%) of methyl2-fluoro-3-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT4-M) as a colorless oil. LCMS-ESI (m/z) calculated for C₁₇H₁₄F₄O₃:342.29; found 343.0 [M+H]+, t_(R)=1.04 min (Method 6). ¹H NMR (400 MHz,CDCl₃-d) δ 7.98-7.91 (m, 1H), 7.77-7.69 (m, 1H), 7.49-7.41 (m, 2H),7.31-7.22 (m, 1H), 7.03-6.92 (m, 1H), 5.40-5.15 (m, 2H), 3.98 (s, 3H),2.34 (s, 3H).

Step 4-18. Synthesis of5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(1-101)

To a solution of INT 4-M (3.0 g, 8.76 mmol) in THE (30 mL) and MeOH (30mL) was added 2 M NaOH (30 mL, 60 mmol). After 12 h at 40° C., the pHwas adjusted to pH 5 with HCl (1M) to produce a solid precipitate thatwas filtered and collected. The resulting product was dissolved in EA(500 mL), dried (Na₂SO₄), filtered and concentrated to provide 2.35 μg(81%) of 5-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoicacid (1-101) as a light yellow solid. LCMS-ESI (m/z) calculated forC₁₆H₁₂F₄O₃: 328.2; found 326.9 [M−H]⁺, t_(R)=0.73 min. (Method 7). ¹HNMR (400 MHz, CD₄OD) δ 7.90-7.82 (m, 1H), 7.74-7.66 (m, 1H), 7.52-7.42(m, 2H), 7.32-7.24 (m, 1H), 7.20-7.13 (m, 1H), 5.44-5.15 (m, 2H), 2.30(s, 3H).

Synthesis of Compound 4-10

Step 4-19. Synthesis of methyl 3-(bromomethyl)-5-methylbenzoate (INT4-N)

To a solution of methyl 3,5-dimethylbenzoate (5 g, 30.5 mmol) in CCl₄(200 mL) were added NBS (5.96 g, 33.5 mmol) and AIBN (1.00 g, 6.1 mmol).After stirring for 12 h at 80° C., the reaction mixture was concentratedand purified by SiO₂ chromatography (PE/EA) to provide 8.4 g (79%) ofcrude methyl 3-(bromomethyl)-5-methylbenzoate (INT 4-N) as a colorlessoil with 70% purity LCMS-ESI (m/z) calculated for C₁₀H₁₁BrO₂: 243.1;found 245 [M+H]⁺, t_(R)=0.873 min. ¹H NMR (400 MHz, CDCl₃-d) δ 7.87 (s,1H), 7.80 (s, 1H), 7.48-7.37 (m, 1H), 4.49 (s, 2H), 3.96-3.89 (m, 4H),2.41 (s, 5H).

Step 4-20. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT4-O)

A mixture of INT 4-N (3 g, 8.64 mmol),2-chloro-4-(trifluoromethyl)phenol (1.7 g, 8.64 mmol) and K₂CO₃ (5.03 g,36.4 mmol) in MeCN (30 mL) was stirred at 60° C. for 12 hr. The reactionmixture was filtered and concentrated to give a residue that waspurified by SiO₂ chromatography (PE/EA) to provide 2.8 g (90%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoate (INT4-0) as a white solid. TLC (5:1 petroleum ether:EA): R_(f)=0.60.LCMS-ESI (m/z) calculated for C₁₇H₁₄ClF₃O₃: 358.7; found 359 [M+H]+,t_(R)=1.06 min.

Step 4-21. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoic acid(4-10)

A mixture of INT 4-0 (2.8 g, 7.81 mmol) and 2M NaOH (30 mL, 30 mmol) inTHE (30 mL) and MeOH (30 mL) was stirred at 30° C. for 12 hr. Thevolatile solvents were removed in vacuo and the resulting solution wasacidified with 1N HCl to pH 5. The resulting precipitate was collectedby filtration and the crude product was triturated with 10:1 PE:EA toprovide 2.1 g (72%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-methylbenzoic acid(Compound 4-10) as a white solid. LCMS-ESI (m/z) calculated forC₁₆H₁₂ClF₃O₃: 344.71; found 342.9 [M+H]⁺, t_(R)=0.761 min. (Method 7).¹H NMR (400 MHz, CD₄OD) δ 8.02-7.95 (m, 1H), 7.86-7.81 (m, 1H),7.75-7.68 (m, 1H), 7.62-7.52 (m, 2H), 7.36-7.27 (m, 1H), 5.29 (s, 2H),2.44 (s, 3H).

The compounds listed in Table 4 were made using the procedures of Scheme4:

TABLE 4 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

4-1  0.67  315.12 312.9 [M − H]⁺ 7

4-2  0.68  315.12 312.9 [M − H]⁺ 7

4-3  0.683 315.12 312.9 [M − H]⁺ 7

4-4  0.74  315.12 313.0 [M − H]⁺ 7

4-5  0.72  327.16 324.9 [M − H]⁺ 7

4-6  0.72  322.14 319.9 [M − H]⁺ 7

4-7  0.92  311.16 313.0 [M + H]⁺ 6

4-8  0.70  326.01 324.9 [M − H]⁺ 7

4-9  0.70  331.57 328.8 [M − H]⁺ 7

4-10 10.80  344.71 367.1 [M + Na]⁺ 3

4-11 10.91  324.30 347.2 [M + Na]⁺ 3

4-12 10.44  292.33 293.2 [M − H]⁺ 4

4-13 10.506 364.68 363.0 [M − H]⁺ 4

4-14 11.007 360.71 359   [M − H]⁺ 4

4-15 10.278 348.68 347.0 [M − H]⁺ 4

4-16 11.354 398.69 397   [M − H]⁺ 4

4-17 10.918 344.71 343   [M − H]⁺ 4

4-18  9.388 349.67 348   [M − H]⁺ 4

4-19 9.223 349.67 348   [M − H]⁺ 4

4-20 11.319 398.69 397   [M − H]⁺ 4

4-21  0.7  330.74 328.9 [M − H]⁺ 7

4-22  0.655 302.32 300.9 [M + H]⁺ 7

4-23  0.663 329.37 330.1 [M − H]⁺ 6

4-24  0.825 349.79 350.1 [M + H]⁺ 6

4-25  0.954 345.75 346   [M + H]⁺ 6

4-26  0.858 336.76 335   [M − H]⁺ 8

4-27  0.873 325.34 324.1 [M − H]⁺ 6

4-28 13.32  314.2  315.2 [M + H]⁺ 9

4-29  3.12  280.7  281.3 [M + H]⁺ 9

Example 5 Synthesis of Compound 5-1 and Other Representative Compounds

Step 5-1. Synthesis of methyl3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B)

To a stirring solution of methyl 3-bromo-5-((2,4-dichlorophenoxy)methyl)benzoate INT 5-A (100 mg, 256.37 μmol, prepared from methyl3-bromo-5-(bromomethyl)benzoate and 2,4-dichlorophenol via Scheme 1) inDMF (2 mL) were added Zn (33.53 mg, 512.75 μmol), Pd₂(dba)₃ (23.48 mg,25.64 μmol), DPPF (28.43 mg, 51.27 μmol), and Zn(CN)₂ (60.21 mg, 512.75μmol, 32.55 μL). The mixture was stirred at 120° C. for 2 h, filtered,concentrated and purified by preparatory thin layer chromatography toafford 60 mg (69.2%) of methyl3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoate (INT 5-B) as a whitesolid. LCMS-ESI (m/z) calculated for C₁₆H₁₁C₁₂NO₃: 336.2; no m/zobserved, t_(R)=1.1 min (Method 6). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s,1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.24-7.17 (m,1H), 6.89 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 3.99 (s, 3H).

Step 5-2. Synthesis of 3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoicacid (Compound 5-1)

To a stirring solution of methyl 3-cyano-5-[(2,4-dichlorophenoxy)methyl]-benzoate (INT 5-B) (60 mg, 178.48 μmol) in MeOH (1 mL) and THE(1 mL) was added NaOH (2 M, 267.72 μL). The mixture was stirred at 10°C. for 16 h then concentrated. The resulting residue was dissolved inH₂O (20 mL) and acidified (1M HCl) to pH 5 and the resulting precipitatewas collected and purified by prep-HPLC to afford 3.2 mg (5.6%) of3-cyano-5-((2,4-dichlorophenoxy)methyl)benzoic acid (Compound 5-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₅H₉Cl₂NO₃: 322.14; found319.9 [M−H]⁺, t_(R)=0.727 min. (Method 6)¹H NMR (400 MHz, DMSO-d₆) δ8.32 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.62 (s, 1H), 7.41 (br d,J=8.8 Hz, 1H), 7.27 (d, J=8.9 Hz, 1H), 5.34-5.32 (m, 1H), 5.35 (s, 1H).

The compounds listed in Table 5 were made using the procedures of Scheme5.

TABLE 5 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

5-1 0.724 322.14 319.9 [M − H]⁺ 7

5-2 0.71  322.14 319.9 [M − H]⁺ 7

Example 6 Synthesis of Compound 6-1

Step 6-1. Synthesis of methyl 2-methoxy-3-methylbenzoate (INT 6-A)

To a solution of 2-hydroxy-3-methyl-benzoic acid (1 g, 6.6 mmol) in DMF(15 mL) was added K₂CO₃ (2.73 g, 19.7 mmol) and CH₃I (4.66 g, 32.86mmol, 2.1 mL). The mixture was stirred at 10° C. for 2 h. AdditionalCH₃I (2.33 g, 16.43 mmol, 1.0 mL) was added and the mixture stirred foran additional 16 h. The reaction mixture was quenched by the addition ofH₂O (50 mL), and then extracted with EA (100 mL×3). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo pressureto give a residue that was purified by SiO₂ chromatography to provide1.0 g (85%) of methyl 2-methoxy-3-methylbenzoate (INT 6-A) as acolorless oil. TLC (33% EA/petroleum ether), R_(f)=0.45. ¹H NMR (400MHz, CDCl₃) δ ppm 2.33 (s, 3H) 3.84 (s, 3H) 3.92 (s, 3H) 7.06 (t, J=7.64Hz, 1H) 7.35 (d, J=7.46 Hz, 1H) 7.64 (d, J=7.70 Hz, 1H).

Step 6-2. Synthesis of 3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoicacid (Compound 6-1)

Compound 6-1 was prepared from INT 6-A according to the procedures ofSchemes 4 and then Scheme 1 to provide 1.0 g (85%) of3-((2,4-dichlorophenoxy)methyl)-2-methoxybenzoic acid (6-1) as acolorless oil. LCMS-ESI (m/z) calculated for C₁₀H₁₂O₃: 180.2; m/z notobserved, t_(R)=0.70 min (Method 7). ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.82 (s, 3H) 5.22 (s, 2H) 7.25 (t, J=7.64 Hz, 1H) 7.30-7.35 (m, 1H)7.37-7.43 (m, 1H) 7.60 (d, J=2.57 Hz, 1H) 7.68 (dd, J=7.52, 1.65 Hz, 1H)7.73 (dd, J=7.76, 1.77 Hz, 1H) 13.03 (br s, 1H).

The compound listed in Table 6 was made using the procedures of Scheme6.

TABLE 6 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

6-1 0.701 327.16 324.9 [M − H]⁺ 7

Example 7 Synthesis of Compound 7-1

Step 7-1. Synthesis of tert-butyl(3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A)

To a stirring solution of 2,4-dichlorophenol (271 mg, 1.67 mmol) in MeCN(7 mL) were added tert-butyl (3-(bromomethyl)benzyl)carbamate (500 mg,1.67 mmol) and K₂CO₃ (299 mg, 2.17 mmol). The flask was sealed, and theresulting white suspension was heated at 60° C. for 3 h. The reactionmixture was cooled to room temperature, diluted with H₂O (10 mL),extracted with Et₂O (2×10 mL), dried (Na₂SO₄), filtered through Celite,and concentrated in vacuo to afford 627 mg (96%) of tert-butyl(3-((2,4-dichlorophenoxy)methyl)benzyl)carbamate (INT 7-A). LCMS-ESI(m/z) calculated for C₁₉H₂₁Cl₂NO₃: 381; found 404.1 [M+Na]⁺, t_(R)=12.2min. (Method 3). ¹H NMR (500 Hz, CDCl₃) 7.37 (d, J=2.5, 1H), 7.34-7.33(m, 3H), 7.25-7.22 (m, 1H), 7.134 (dd, J=9.0, 2.5, 1H), 6.858 (d, J=9.0,1H), 5.10 (s, 2H), 4.33 (d, J=5.5, 2H), 1.45 (s, 9H).

Step 7-2. Synthesis of(3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (Compound 7-1)

To a stirring solution of tert-butyl (3-((2,4-dichlorophenoxy)methyl)-benzyl) carbamate (INT 7-A) (200 mg, 523 μmol) in dioxane (5 mL)was added 4M Hydrogen chloride in dioxanes (5 mL, 20.9 mmol). After 3 h,the reaction mixture became a suspension and was filtered. The filtratewas concentrated to afford 101 mg of crude white solid that wasrecrystallized from EtOH (0.7 mL) to afford 15.5 mg (10.5%) of(3-((2,4-dichlorophenoxy)methyl)phenyl)methanamine (Compound 7-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₄H₁₃C₂NO. 281; found 282.1[M+H]⁺, t_(R)=6.345 min. (Method 3). ¹H NMR (500 Hz, DMSO-d6) 8.26 (brs, 3H), 7.61 (d, J=3.0, 1H), 7.55 (s, 1H), 7.49-7.47 (m, 3H), 7.39 (dd,J=9.0, 2.5, 1H), 7.28 (d, J=9.0, 1H), 5.22 (s, 2H), 4.05 (s, 2H).

The compound listed in the Table 7 was made using the procedures ofScheme 7.

TABLE 7 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

7-1 6.35 282.16 282.1 [M − H]⁺ 4

Example 8 Synthesis of Compound 8-1 and Other Representative Compounds

Step 8-1. Synthesis of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A)

To a solution of methyl 2-iodo-5-methyl-benzoate (1 g, 3.62 mmol) inCCl₄ (10 mL) were added NBS (644.7 mg, 3.62 mmol) and AIBN (11.9 mg,72.5 μmol). The mixture was stirred at 100° C. for 2 h and wasconcentrated under reduced pressure to give a residue that was purifiedby flash SiO₂ chromatography (EA/petroleum ether) to afford 733 mg(57.0%) of methyl 5-(bromomethyl)-2-iodobenzoate (INT 8-A) as a brownsolid. TLC: (10% EA/Petroleum ether) R_(f): 0.5. ¹H NMR (400 MHz, CDCl₃)δ 7.98 (d, J=8.1 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.20 (dd, J=2.3, 8.1Hz, 1H), 4.46-4.43 (m, 2H), 3.95 (s, 3H).

Step 8-2. Synthesis of methyl5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoate (INT 8-B)

To a solution of methyl 5-(bromomethyl)-2-iodo-benzoate (INT 8-A) (733mg, 2.06 mmol) in MeCN (5 mL) were added K₂CO₃ (571 mg, 4.13 mmol) and2,4-dichlorophenol (337 mg, 2.06 mmol). After stirring at 50° C. for 16h the reaction mixture was concentrated in vacuo and was purified byflash SiO₂ chromatography to provide 780 mg, (86.4%) yield methyl5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoate (INT 8-B) as a whitesolid. TLC: (10% EA/Petroleum ether) R: 0.3. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.2 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H),7.30-7.28 (m, 1H), 7.17 (dd, J=2.4, 8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H),5.10 (s, 2H), 3.96 (s, 3H).

Step 8-3. Synthesis of methyl5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoate (INT 8-C)

To a solution of methyl 5-((2,4-dichlorophenoxy)methyl)-2-iodo-benzoate(INT 8-B) (200 mg, 457.6 μmol) in dioxane (1 mL) and H₂O (1 mL) wereadded Pd(dppf)Cl₂ (16.7 mg, 22.9 μmol), K₂CO₃ (189.7 mg, 1.4 mmol), andMeB(OH)₂ (54.8 mg, 915 μmol). The mixture was stirred at 100° C. for 2hr, concentrated and purified by flash SiO₂ chromatography (EA/petroleumether) to provide 100 mg (67.2%) of methyl5-((2,4-dichlorophenoxy)methyl)-2-methyl-benzoate (INT 8-C) as a whitesolid. TLC: (10% EA/Petroleum ether) R_(f)=0.4. ¹H NMR (400 MHz, CDCl₃)δ 7.98 (d, J=1.6 Hz, 1H), 7.51 (dd, J=1.7, 7.8 Hz, 1H), 7.40 (d, J=2.6Hz, 1H), 7.31-7.28 (m, 1H), 7.16 (dd, J=2.4, 8.8 Hz, 1H), 6.88 (d, J=8.8Hz, 1H), 5.12 (s, 2H), 3.96-3.90 (m, 3H), 2.61 (s, 3H).

Step 8-4. Synthesis of 5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoicacid (Compound 8-1′

To a solution of methyl 5-[(2,4-dichlorophenoxy)methyl]-2-methyl-benzoate (INT 8-C) (100 mg, 307.52 μmol) in MeOH (1 mL)and THF (1 mL) was added NaOH (2 M, 461.27 μL). After stirring at 10° C.for 16 h the mixture was concentrated in vacuo and purified by prep-HPLCto provide 29 mg (30.3%) of5-((2,4-dichlorophenoxy)methyl)-2-methylbenzoic acid (Compound 8-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₅H₁₂Cl₂O₃: 310.02; found308.9 [M−H]⁺, t_(R)=0.718 min. (Method 7). ¹H NMR (400 MHz, CDCl₃) δ8.12 (s, 1H), 7.57 (br d, J=7.9 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.32(d, J=7.5 Hz, 1H), 7.17 (dd, J=2.4, 8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H),5.14 (s, 2H), 2.67 (s, 3H).

The compounds listed in Table 8 were made using the procedures of Scheme8.

TABLE 8 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

8-1  0.72  311.16 308.9 [M − H]⁺ 7

8-2  0.724 311.16 308.9 [M − H]⁺ 7

8-3 10.326 371.74 370   [M − H]⁺ 4

8-4 11.819 406.79 405   [M − H]⁺ 4

Example 9 Synthesis of Compound 9-1

Step 9-1. Synthesis of methyl 4-bromo-6-(hydroxymethyl)picolinate (INT9-A)

To a stirring solution of dimethyl 4-bromopyridine-2,6-dicarboxylate(1.0 g, 3.6 mmol) in MeOH (12 mL) and DCM (6 mL) at 0° C. was addedsodium borohydride (0.17 g, 4.4 mmol) in 3 portions. The reactionmixture was warmed to room temperature and stirred overnight. Additionalsodium borohydride (0.17 g, 4.4 mmol) was added. After 2 h, the reactionmixture was diluted with NH₄Cl (aq) (10 mL) and DCM (10 mL). The aqueouslayer was extracted with DCM (2×10 mL) and EA (10 mL), dried (Na₂SO₄),filtered through Celite, and concentrated in vacuo to afford a crudewhite solid that was purified by SiO₂ chromatography (10% MeOH inEA/hexanes) to afford 514 mg, (57%) of methyl4-bromo-6-(hydroxymethyl)picolinate (INT 9-A) as a white solid. LCMS-ESI(m/z) calculated for C₉H₁₀BrNO₃: 258.98; m/z not observed, t_(R)=3.21min. (Method 1).

Step 9-2. Synthesis of methyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)picolinate (INT9-B)

To a stirring solution of 2-chloro-4-(trifluoromethyl)phenol (87.9 mg,0.447 mmol) in TH (10 mL) were added methyl 4-bromo-6-(hydroxymethyl)picolinate (INT 9-A) (100 mg, 0.406 mmol), triphenylphosphine (107 mg,0.406 mmol) and TEA (56.7 μL, 406 μmol). The reaction mixture was cooledto 0° C. and diisopropyl azodicarboxylate (82.2 mg, 80.0 μL, 0.406 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 30minutes, warmed to room temperature and stirred overnight. The reactionmixture was concentrated in vacuo to afford a crude product that waspurified by SiO₂ chromatography (EA/hexanes) to afford 94 mg (55%) ofmethyl 4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate(INT 9-B) as an off-white solid. LCMS-ESI (m/z) calculated forC₁₅H₁₀BrClF₃NO₃: 422.95; m/z not observed, t_(R)=6.73 min. (Method 1).

Step 9-3. Synthesis of4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid(Compound 9-1)

To a stirring solution of methyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT9-B) (94.5 mg, 223 μmol) in THE (2 mL) was added 1M NaOH (1 mL, 1.11mmol). The reaction mixture was heated at 60° C. overnight, cooled andacidified with 3M HCl. The mixture was extracted with EA and Et₂O, andthe combined organics were dried (Na₂SO₄), filtered and concentrated invacuo to afford 77.6 mg (85%) of4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid(Compound 9-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₄H₁₈BrClF₃NO₃: 408.93; found 410.0 [M+H]⁺, t_(R)=10.7 min. (Method 3).

The compounds listed in Table 9 were made using the procedures of Scheme9:

TABLE 9 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

9-1 10.73  410.57 412.0 [M + H]⁺ 3

9-2 10.758 328.26 327   [M − H]⁺ 4

9-3 10.281 296.30 295.2 [M − H]⁺ 4

Example 10 Synthesis of Compound 10-1

Step 10-1. Synthesis of methyl3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-benzoate (INT 10-A)

Into a pressure vessel containing a solution of methyl 3-(hydroxymethyl)benzoate (499 mg, 3.00 mmol) in 1,4-Dioxane (9 mL) were added2-chloro-5-(trifluoromethyl) pyridine (363 mg, 2.00 mmol) and potassiumtert-butoxide (337 mg, 3.00 mmol). The vessel was sealed, and thereaction mixture was heated and stirred overnight at 90° C., then cooledto room temperature. The reaction mixture was partitioned between Et₂Oand H₂O. The phases were separated and the aqueous layer was furtherextracted with diethyl ether (2×). The organic phases were combined,washed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The resulting colorless oil was purified by flash SiO₂chromatography (EA/hexanes) to yield 177 mg (28.4%) of methyl3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 10-A) as acolorless oil. LCMS-ESI (m/z) calculated for C₁₅H₁₂F₃NO₃: 311.1; found312.1 [M+H]⁺, t_(R)=6.25 min. (Method 1). ¹H NMR (500 MHz, DMSO-d6) δ8.608 (s, 1H), 8.114 (dd, J=8.5, 2.5 Hz, 1H), 8.050 (s, 1H), 7.934 (d,J=7.5 Hz, 1H), 7.753 (d, J=8.0 Hz, 1H), 7.551 (t, J=7.5 Hz, 1H), 7.129(d, J=9.0 Hz, 1H), 5.512 (s, 2H), 3.858 (s, 3H). ¹⁹F NMR (470 MHz,DMSO-d6) δ 60.140 (s).

Step 10-2. Synthesis of3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound10-1)

A 20 mL vial containing a stirring solution of methyl3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT 10-A) (177mg, 0.569 mmol) in THE (6 mL) was charged with 1M NaOH (2.27 mL, 2.27mmol). After stirring for 12 h at 50° C. the reaction mixture wasconcentrated in vacuo and the residue was dissolved in H₂O and acidifiedto pH 4-5 using 3M HCl. The resulting white precipitate was extractedwith Et₂O (3×). The combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated in vacuo to yield 151 mg (89.3%) of3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound10-1) as a white solid. LCMS-ESI (m/z) calculated for C₁₄H₁₁F₃NO₃:297.2; found 298.1 [M+H]⁺, t_(R)=9.33 min. (Method 3). ¹H NMR (500 MHz,DMSO-d₆) δ 13.006 (br s, 1H), 8.595 (s, 1H), 8.100 (dd, J=9.0, 2.5 Hz,1H), 8.015 (s, 1H), 7.900 (d, J=8.0 Hz, 1H), 7.702 (d, 8.0 Hz, 1H),7.522 (t, J=7.5 Hz, 1H), 7.115 (d, J=8.5 Hz, 1H), 5.493 (s, 2H). ¹⁹F NMR(470 MHz, DMSO-d6) δ 60.126 (s).

The compound listed in Table 10 was made using the procedures of Scheme10:

TABLE 10 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

10-1 9.33 297.23 298.2 [M + H]⁺ 3

Example 11 Synthesis of Compound 11-1

Step 11-1. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate(INT 11-B)

To a degassed solution of methyl3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzoate (INT11-A) (200 mg, 472 μmol, prepared via Scheme 2 from methyl3-bromo-5-(hydroxymethyl)benzoate and2-chloro-4-(trifluoromethyl)phenol)), tricyclohexyl phosphine (6.62 mg,23.6 μmol), potassium phosphate (230 mg, 1.09 mmol), andcyclopropylboronic acid (52.7 mg, 614 μmol) in toluene (4 mL) was addedpalladium diacetate (5.30 mg, 23.6 μmol). The reaction vial was cappedand heated at 100° C. overnight. The reaction was further degassed andadditional tricyclohexyl phosphine (6.62 mg, 23.6 μmol),cyclopropylboronic acid (52.7 mg, 614 μmol), and palladium diacetate(5.30 mg, 23.6 μmol) were added. After heating at 100° C. for 4 h, thereaction mixture was filtered through Celite rinsing with EA andconcentrated in vacuo. The residue was taken up in EA, washed with sat.sodium bicarbonate and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to afford crude material that was purified by SiO₂chromatography (EA/hexanes) to afford 132 mg (72%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate(INT 11-B). LCMS-ESI (m/z) calculated for C₁₉H₁₆ClF₃O₃: 384.1; no m/zobserved, t_(R)=7.02 min. (Method 1). ¹H NMR (500 Hz, DMSO-d6) δ 7.86(d, J=2.5, 1H), 7.85 (s, 1H), 7.71 (dd, J=8.8, 2.5, 1H), 7.64 (s, 1H),7.46, (s, 1H), 7.41 (d, J=9.0, 1H), 5.35 (s, 2H), 3.85 (s, 3H),2.07-2.02 (m, 1H), 1.03-1.00 (m, 2H), 0.73-0.70 (m, 2H).

Step 11-2 Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoicacid (Compound 11-1)

To a stirring solution of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoate(INT 11-B, 132 mg, 0.343 mmol) in THE (2 mL) was added 1M NaOH (2 mL,1.72 mmol). After heating at 60° C. overnight, the reaction mixture wascooled and acidified with 3M HCl. The mixture was extracted with EA andEt₂O, dried (Na₂SO₄), filtered, concentrated in vacuo. The crude solidwas purified by reversed phase HPLC to afford 71.2 mg (56%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyclopropylbenzoicacid (Compound 11-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₈H₁₄ClF₃O₃: 370.7; found 393.1 [M+Na]⁺, t_(R)=11.25 min. (Method 3).¹H NMR (500 Hz, DMSO-d₆) δ 13.00 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H),7.71 (d, J=8.0, 1H), 7.62 (s, 1H), 7.43-7.41 (m, 2H), 5.34 (s, 2H), 2.04(m, 1H), 1.01 (d, J=7.0, 2H), 0.72-0.71 (m, 2H).

The compound listed in the Table 11 was made using the procedures ofScheme 11.

TABLE 11 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

11-1 11.25 370.75 393.1 [M + Na]⁺ 3

Example 12 Synthesis of Compound 12-1

Step 12-1. Synthesis of methyl3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A)

To a stirring solution of methyl 3-(bromomethyl)benzoate (300 mg, 1.31mmol) and 2,4-dichloroaniline (0.23 g, 1.44 mmol) in DMF (2 mL) at 0° C.was added NaH (60% in mineral oil, 38 mg, 0.95 mmol). After 1 at 0° C.the mixture was diluted with H₂O (20 mL) and extracted with EA (2×50mL). The organic layers were combined, washed with brine, dried(Na₂SO₄), filtered, and concentrated to provide a crude product that waspurified by SiO₂ chromatography to afford 230 mg (56%) of methyl3-(((2,4-dichlorophenyl) amino)methyl)benzoate (INT 12-A) that was 30%pure and used without further purification. LCMS-ESI (m/z) calculatedfor C₁₅H₁₃Cl₂NO₂: 310.2; found 311.2 [M+H]⁺, t_(R)=5.7 min. (Method 11).

Step 12-2. Synthesis of 3-(((2,4-dichlorophenyl)amino)methyl)benzoicacid (Compound 12-1)

To a stirring solution of crude methyl 3-(((2,4-dichlorophenyl)amino)methyl)benzoate (INT 12-A) (230 mg, 0.74 mmol) in MeOH (3 mL) wasadded a solution of NaOH (290 mg, 7.4 mmol) in H₂O (1 mL). The reactionwas heated to reflux for 2, cooled to rt and concentrated in vacuo toremove the MeOH. The aqueous layer was acidified to pH 2 with 4N HCl(aq)and extracted with EA (2×50 mL). The combined organic layers were washedwith H₂O, brine, dried (MgSO₄), filtered and concentrated in vacuo toprovide a crude material that was purified by SiO₂ chromatography toprovide 5 mg (2.3%) of 3-(((2,4-dichlorophenyl)amino)methyl)benzoic acid(Compound 12-1). LCMS-ESI (m/z) calculated for C₁₄H₁₁CnNO₂. 296.2; found296.5 [M+H]⁺, t_(R)=13.88 min. (Method 9). ¹H NMR (400 MHz, DMSO-d₆) δ7.88 (s, 1H), 7.76 (d, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.35 (m, 2H),7.06 (d, J=8 Hz, 1H), 6.51 (d, J=8 Hz, 1H), 6.39 (t, J=8 Hz, 1H), 4.43(d, J=4 Hz, 2H).

The compounds listed in Table 12 were made using the procedures ofScheme 12.

TABLE 12 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

12-1 13.88  296.2 296.5 [M + H]⁺ 10

12-2  0.787 277.3 275.9 [M + H]⁺  6

12-3  0.913 330.7 331.1 [M + H]⁺  6

12-4  0.984 329.7 330.1 [M + H]⁺  6

Example 13 Synthesis of Compound 13-1

Step 13-1. Synthesis of 3-((2,3-dichlorophenoxy)methyl)benzamide(Compound 13-1)

To a stirring solution INT 13-1 (0.3 g, 1.1 mmol, prepared via Scheme 3from 3-(bromomethyl)benzonitrile and 2,3-dichlorophenol) in MeOH (5 mL)was added to a solution of NaOH (0.34 g, 8.6 mmol) in H₂O (5 mL). Afterheating for 4 h at 90° C., the reaction mixture was cooled to roomtemperature and the resulting solid was collected and washed with H₂O(10 mL). The material was dried under high vacuum to provide 68.8 mg(21%) of 3-((2,3-dichlorophenoxy)methyl)benzamide (Compound 13-1).LCMS-ESI (m/z) calculated for C₁₄H₁₁Cl₂NO₂: 296.2; found 297.2[M+H]⁺,t_(R)=11.8 min. (Method 10). ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H),7.78 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 7.10(m, 2H), 6.86 (d, J=8 Hz, 1H), 6.22 (bs, 1H), 5.59 (bs, 1H), 5.21 (s,2H).

The compound listed in Table 13 was made using the procedures of Scheme13.

TABLE 13 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

13-1 11.83 296.15 296.5 [M − H]⁺ 4

Example 14 Synthesis of Compound 14-1

Step 14-1. Synthesis of (3-((2,4-dichlorophenoxy)methyl)phenyl)methanol(Compound 14-1)

To a stirring solution of 2,4-dichlorophenol (324 mg, 1.99 mmol) in THF(15 mL) were added 1,3-phenylenedimethanol (250 mg, 1.81 mmol),triphenylphosphine (475 mg, 1.81 mmol), and TEA (183 mg, 252 μL, 1.81mmol). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (356 μL, 1.81 mmol) was added dropwise. The reactionmixture was stirred at 0° C. for 30 minutes, warmed to room temperature,and stirred overnight. The reaction mixture was concentrated in vacuo toafford crude product that was purified by SiO₂ chromatography(EA/hexanes) to afford 90.9 mg (17.7%) of(3-((2,4-dichlorophenoxy)methyl)phenyl)methanol (Compound 14-1) as anoff-white solid. LCMS-ESI (m/z) calculated for C₁₄H₁₂Cl₂O₂: 282.0; found282.21 [M+H]⁺, t_(R)=10.08 min. (Method 3).

The compound listed in Table 14 was made using the procedures of Scheme14:

TABLE 14 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

14-1 10.05 283.15 283.0 [M − H]⁺ 4

Example 15 Synthesis of Compound 15-1

Step 15-1. Synthesis of methyl3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A)

To a stirring solution of 2,4-dichlorobenzenethiol (750 mg, 4.19 mmol)in MeCN (20 mL) were added methyl 3-(bromomethyl)benzoate (959 mg, 4.19mmol) and potassium carbonate (753 mg, 5.45 mmol). The reaction mixturewas heated at 60° C. for 3 h, cooled to room temperature, diluted withH₂O (20 mL) and extracted with Et₂O (2×20 mL). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated to afford 1.3 g(94%) of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A)as a yellow oil that solidified upon standing. LCMS-ESI (m/z) calculatedfor C₁₅H₁₂Cl₂O₂S: 325.9; found 327.1 [M+H]+, t_(R)=12.5 min. (Method 3).

Step 15-2. Synthesis of 3-(((2,4-dichlorophenyl)thio)methyl)benzoic acid(15-1)

To a stirring solution of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) (250 mg, 0.764 mmol) in THE (3 mL) wasadded 1M NaOH (4 mL, 3.82 mmol). The reaction mixture was heated at 60°C. for 3 h, the aqueous layer extracted with EA (2×5 mL), dried(Na₂SO₄), filtered and concentrated to give a crude solid that waspurified by reversed phase HPLC to afford 240.3 mg (99%) of3-(((2,4-dichlorophenyl)thio)methyl)benzoic acid (Compound 15-1) as anoff-white solid. LCMS-ESI (m/z) calculated for C₁₄H₁₀Cl₂O₂S: 311.97;found 313.1 [M+Na]⁺, t_(R)=10.59 min. (Method 3).

The compound listed in Table 15 was made using the procedures of Scheme15.

TABLE 15 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

15-1 10.59 313.19 313.1 [M − H]⁺ 4

Example 16 Synthesis of Compound 16-1 and Other Representative Compounds

Step 16-1. Synthesis of methyl 3-(2,4-dichlorophenoxy)benzoate (INT16-A)

To a stirring solution of (3-(methoxycarbonyl)phenyl)boronic acid (221mg, 1.2 mmol) and 2,4-dichlorophenol (100 mg, 0.61 mmol) in anhydrousDCM (5 mL) were added Cu(OAc)₂ (111 mg, 0.61 mmol) and TEA (0.86 mL,0.61 mmol). After stirring overnight, the reaction mixture was filtered,concentrated and purified by SiO₂ chromatography (EA/hexane) to afford182 mg (27%) of methyl 3-(2,4-dichlorophenoxy) benzoate (INT 16-A).LCMS-ESI (m/z) calculated for C₁₄H₁₀Cl₂O₃: 296; found 297.5 [M+H]⁺,t_(R)=5.96 min. (Method 11).

Step 16-2. Synthesis of 3-(2,4-dichlorophenoxy)benzoic acid (16-1)

To a stirring solution of methyl 3-(2,4-dichlorophenoxy)benzoate (INT16-A) (50 mg, 0.17 mmol) in MeOH (3 mL) was added 1M NaOH (67 mg, 1.68mmol). The reaction mixture was heated at reflux for 2 h. The pH wasadjusted to 2 by the addition of 4N HCl (aq) and was then extracted withEA. The organic layer was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo to give a crude solid that was purified by SiO₂chromatography (EA/hexanes) to afford 10 mg (21%)3-(2,4-dichlorophenoxy)benzoic acid (Compound 16-1) as a white solid.LCMS-ESI (m/z) calculated for C₁₃H₈Cl₂O₃: 281.99; found 283.6 [M+H]⁺,t_(R)=14.15 min. (Method 10).

The compounds listed in Table 16 were made using the procedures ofScheme 16.

TABLE 16 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

16-1 14.15 283.10 283.6 [M—H]⁺ 10

16-2 13.46 293.66 294.4 [M—H]⁺ 10

Example 17 Synthesis of Compound 17-1, Compound I-31 and OtherRepresentative Tetrazole Isostere Compounds

Step 17-1: 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile(INT-17-1)

A mixture of 3-(bromomethyl)benzonitrile (500 mg, 2.55 mmol),2-chloro-4-(trifluoromethyl)phenol (0.551 g, 2.81 mmol), and K₂CO₃ (1.06g, 7.65 mmol) in acetone (10.0 mL) was heated at 80° C. for 1 hour. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (40 gcartridge), eluting with a mixture of hexanes and EA to provide 750 mg(94%) of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzonitrile(Compound 17-1) as a solid. ¹HNMR (400 MHz, DMSO) δ 7.96-7.92 (m, 1H),7.90-7.87 (m, 1H), 7.87-7.80 (m, 2H), 7.72 (ddd, J=8.7, 2.3, 0.7 Hz,1H), 7.66 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 5.38 (s, 2H); LCMS:m/z (ES−), [M−H]⁺: 310.15; HPLC t_(R)=5.78 min. (Method 12).

Step 17-2:5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole(INT-31)

A mixture of Compound 17-1 (100 mg, 0.321 mmol), NaN₃ (31.3 mg, 0.481mmol), and NH₄Cl (27.5 mg, 0.513 mmol) in DMF (1.00 mL) was heated at130° C. for 12 hours. The mixture was cooled to room temperature andpoured into 2M HCl at 0° C. The mixture was filtered, and the solid wasdried to provide5-(3-((2-chloro-4-(trifluoromethyl)-phenoxy)methyl)phenyl)-1H-1,2,3,4-tetrazole(INT-31) as a solid (102 mg, 90%). ¹HNMR (400 MHz, CD₃OD) δ 8.17 (s,1H), 8.00 (d, J=7.8 Hz, 1H), 7.72 (dd, J=8.1, 5.0 Hz, 2H), 7.67-7.53 (n,2H), 7.33 (d, J=8.7 Hz, 1H), 5.37 (s, 2H); LCMS: calculated forC₁₅H₁₀ClF₃N₄O: 354; found 355.06, [M−H]+, t_(R)=4.35 min. (Method 12).

The compounds listed in Table 17 were made using the procedures ofScheme 17.

TABLE 17 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

17-1 5.76 311.69 309.99 [M—H]⁺ 12

17-2 9.89 354.72 355.1 [M + H]⁺  3

17-3 9.98 354.72 355 [M + H]⁺  3

17-4 10.34 355.60 355 [M + H]⁺  3

17-5 9.49 302.34 303.2 [M + H]⁺  3

17-6 9.792 355.71 356.1 [M + H]⁺  3

17-7 8.991 304.71 303 [M + H]⁺  3

17-8 10.167 370.72 369 [M—H]⁺  4

17-9 9.557 338.27 337.2 [M—H]⁺  4

17-10 10.263 370.72 369 [M—H]⁺  4

17-11 10.06 334.30 333.2 [M—H]⁺  4

17-12 9.905 354.72 355.1 [M + H]⁺  3

17-13 9.879 300.75 300.1 [M + H]⁺  3

17-14 10.482 372.71 373.1 [M + H]⁺  3

17-15 10.09 372.71 373.1 [M + H]⁺  3

17-16 10.04 372.71 373.1 [M + H]⁺  3

Example 18 General Synthesis of Representative Arylsulfonamide IsostereCompounds

A solution of 3-aminobenzyl alcohol in DMF is treated with NaH andbenzyl bromide to form 3-((benzyloxy)methyl)aniline. After isolation,3-((benzyloxy)-methyl)aniline is dissolved in CH₂Cl₂, treated withpyridine and an arylsulfonyl chloride (ArSO₂Cl) to give the O-benzylprotected arylsulfonamide which is deprotected by catalytichydrogenation to give alcohol Intermediate 18-A. Preparation of thefinal compound is accomplished according to the Mitsunobu conditionsdescribed in Scheme 2, step 1.

Example 19 General Synthesis of Representative Sulfonylurea IsostereCompounds

A solution of 3-bromobenzyl alcohol in DMF is treated with NaH andbenzylbromide to form 1-((benzyloxy)methyl)-3-bromobenzene that isconverted to a Grignard reagent in a separate step by dissolving in dryTHE and treating with Mg. The Grignard reagent is reacted with DABSO,sulfuryl chloride and ammonium hydroxide according to Woolven, H. et al.(Org. Lett. 13:4876, 2011) to provide the O-benzyl protectedsulfonamide, Intermediate 19-A. INT 19-A is treated with base, DPPA andacetic acid according to the method of Lockhurst, C. A. et al. (Tet.Lett. 48:8878, 2007) to provide the O-benzyl protected sulfonylurea,Intermediate 19-B. INT 19-B is deprotected by catalytic hydrogenation togive the free alcohol intermediate that is converted to the finalcompound according to the Mitsunobu conditions described in Scheme 2,step 1.

Example 20 General Synthesis of Representative N-AcylsulfonamideIsostere Compounds

Intermediate 19-A (see Example 19) is reacted with ZnCl₂ and aceticanhydride (Ac₂O) according to Pham, M. V. et al. (Angew. Chem I.E.51:10610, 2012) to provide an O-benzyl protected N-acylsulfonamideintermediate that is deprotected by catalytic hydrogenation to give thefree alcohol, Intermediate 20-A. The alcohol is converted to the finalcompound according to the Mitsunobu conditions described in Scheme 2,step 1.

Example 21 General Synthesis of Representative N-hydroxyamide IsostereCompounds

A compound of Formula (I) wherein A is phenyl and R is carboxylic acidis dissolved in DMF and cooled to 0° C. Ethyl chloroformate (1.2 eq.)and N-methyl morpholine (1.3 eq.) are added successively and mixture isstirred 10 minutes. Hydroxylamine (2 eq.) in methanol is added and thereaction is allowed to warm to room temperature and stir overnight.Routine workup and purification gives the desired N-hydroxyamideproduct.

Example 22 General Synthesis of Representative Phosphinc Acid IsostereCompounds

3-Iodobenzyl alcohol is converted to Intermediate 22-A according to theMitsunobu conditions described in Scheme 2, step 1. The aryl iodide isconverted to an alkylphosphinate using a palladium catalyzed crosscoupling reaction (Pd(OAc)₂ and PPh₃ as ligand) described by Grady, H.L. (“Preparation of arylphosphinic acid derivatives as building blocksfor binding sites”, Retrospective Theses and Dissertations, 10373, 1992)that uses methyl phosphinate in acetonitrile in the presence of NMM as abase. The aryl phosphinic acid product is obtained from hydrolysis ofthe alkylphosphinate in aqueous HCl.

Example 23 General Synthesis of Representative Phosphonic Acid IsostereCompounds

3-Bromobenzyl alcohol is converted to Intermediate 23-A according to theMitsunobu conditions described in Scheme 2, step 1. The aryl bromide isconverted to a dialkylphosphonate using a palladium catalyzed crosscoupling reaction (Pd(OAc)₂ and CM-Phos as ligand) described by Fu, C.W. et al. (Org. Lett. 17:5906, 2015) that uses diisopropylphosphite inalcohol solvent with DIPEA as a base. The aryl phosphonic acid productis achieved from hydrolysis of the dialkylphosphonate in aqueous HCl.

Example 24 General Synthesis of Representative Pyrrolidine-2,4-dioneIsostere Compounds

Conversion of the starting phenyl glycine amino acid derivative to thePyrrolidine-2,4-dione is accomplished by a three-stepaddition/cyclization/decarboxylation sequence described inWO2007/063010, to give Intermediate 24-A. This intermediate isdeprotected by catalytic hydrogenation to give the free alcohol that isconverted to the final compound according to the Mitsunobu conditionsdescribed in Scheme 2, step 1. The starting material, amino acid methylester can be prepared in various ways known to those skilled in the art;for example from 3-((benzyloxy)methyl)benzaldehyde (described below) bya Strecker amino acid synthesis and esterification.

Example 25 General Synthesis of Representative Furan-2,4-dione IsostereCompounds

Commercially available 3-hydroxymethyl benzaldehyde is reacted with NaHand benzylbromide to form 3-((benzyloxy)methyl)benzaldehyde. Thisintermediate is converted to the cyclopentane-1,3-dione in a two-stepsequence described in WO2007/063010, to give Intermediate 25-A. Thisintermediate is deprotected by catalytic hydrogenation to give the freealcohol that is converted to the final compound according to theMitsunobu conditions described in Scheme 2, step 1.

Example 26 General Synthesis of Representative Cyclopentane-1,3-dioneIsostere Compounds

A solution of 3-bromobenzyl alcohol in DMF is treated with NaH andbenzylbromide to form 1-((benzyloxy)methyl)-3-bromobenzene. Thisintermediate is converted to the cyclopentane-1,3-dione in a three-step,conjugate addition/deprotection/oxidation sequence described byLassalas, P. et al. (ACS Med. Chem. Lett. 8:864, 2017) to giveIntermediate 26-A. This intermediate is deprotected by catalytichydrogenation to give the free alcohol that is converted to the finalcompound according to the Mitsunobu conditions described in Scheme 2,step 1.

Example 27 General Synthesis of Representative Difluorophenol IsostereCompounds

3-Bromobenzyl alcohol and commercially available4-hydroxy-3,5-difluorophenylboronic acid are coupled according to theSuzuki coupling method described in Example 11 to give Intermediate 27-Athat is converted to the final compound according to the Mitsunobuconditions described in Scheme 2, step 1.

Example 28 General Synthesis of Representative 3-Substituted5-Oxo-Thiadiazole Isostere Compounds

A solution of 3-cyanobenzyl alcohol in DMF is treated with NaH andbenzylbromide to form 3-((benzyloxy)methyl)benzonitrile. The arylcyanide is then converted to the 3-Substituted 5-Oxo-Thiadiazole in twosteps according to Kohara, Y. et al. (J. Hetercyclic Chem. 37:1419,2000) to give Intermediate 28-A. This intermediate is deprotected bycatalytic hydrogenation to give the free alcohol that is converted tothe final compound according to the Mitsunobu conditions described inScheme 2, step 1.

Example 29 General Synthesis of Representative 3-SubstitutedOxadiazoline Isostere Compounds

A solution of 3-cyanobenzyl alcohol in DMF is treated with NaH andbenzylbromide to form 3-((benzyloxy)methyl)benzonitrile. The arylcyanide is then converted to the 3-substituted oxadiazolone in two stepsaccording to Yu, X. et al. (Org. Lett. 18:5412, 2-016) to giveIntermediate 29-A. This intermediate is deprotected by catalytichydrogenation to give the free alcohol that is converted to the finalcompound according to the Mitsunobu conditions described in Scheme 2,step 1.

Example 30 General Synthesis of Representative Thiazolidine 2,4-dioneIsostere Compounds

Commercially available 3-hydroxymethyl benzaldehyde is reacted with NaHand benzylbromide to form 3-((benzyloxy)methyl)benzaldehyde. Theresulting ether aldehyde is converted to the mandelate according toSirimanne and Patterson (J. Label. Cmpd. Radiopharm. 33:725, 1993) tofirst give a mandelic acid derivative that is esterified givingIntermediate 30-A. Intermediate 30-A is converted to thethiazolidine-2,4-dione according to Koyama et al. (Biorg. Med. Chem.Lett. 13:1801, 2003) and catalytic hydrogenation allows deprotection ofthe alcohol to give Intermediate 30-B. Alcohol 30-B is converted to thefinal compound according to the Mitsunobu conditions described in Scheme2, step 1.

Example 31 Alternative Synthesis of Compound 1-56 and Synthesis of 31-2

Step 31-1. Synthesis of methyl 6-(hydroxymethyl)picolinate (INT 31-A)

To a stirring solution of dimethyl pyridine-2,6-dicarboxylate (20 g,102.5 mmol) in MeOH (20 mL) at 0° C. was added sodium borohydride (5.81g, 153.7 mmol) in 3 portions. The reaction mixture was warmed to roomtemperature and stirred for 1 h. The reaction mixture was diluted withNH₄Cl (aq) (10 mL) and extracted with EA (3×500 mL) and EA (10 mL). Thecombined organic layers were dried (Na₂SO₄), concentrated in vacuo andpurified by SiO₂ chromatography (10% MeOH in EA/hexanes) to afford 12 g,(70%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (INT 31-A) as awhite solid. TLC (EA): R_(f)=0.60.

Step 31-2. Synthesis of methyl 6-(chloromethyl)picolinate (INT 31-B)

A flask containing a stirring solution of INT 31-A (5.00 g, 29.9 mmol)in DCM (62.5 mL) was charged with thionyl chloride (4.36 mL, 59.8 mmol)at room temperature. After stirring for 14 h, the reaction mixture wascharged dropwise with saturated aqueous K₂CO₃ to adjust the pH to 10-11.The organic layer was collected, and the aqueous layer wasback-extracted 2× with DCM. The organic layers were combined, washedwith brine, dried (Na₂SO₄) and purified by SiO₂ chromatography(EA/hexanes) to provide 3.9 g (69.7%) of methyl6-(chloromethyl)picolinate (INT 31-B) as a colorless oil that solidifiedupon standing to yield a white crystalline powder. LCMS-ESI (m/z)calculated for C₈H₈ClNO₂: 185.61; m/z 186.1 (M+H)⁺, t_(R)=3.64 min.(Method 1). ¹H NMR (500 MHz, DMSO-d6) δ 8.09-7.99 (m, 2H), 7.81 (dd,J=7.5, 1.3 Hz, 1H), 4.86 (s, 2H), 3.89 (s, 3H).

Step 31-3. Synthesis of methyl6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (Compound31-C)

A flask containing INT 31-C (3.861 g, 20.8 mmol) was charged with asolution of 2-chloro-4-(trifluoromethyl)phenol (4.497 g, 22.9 mmol) inMeCN (70 mL), followed by K₂CO₃ (4.312 g, 31.2 mmol) and potassiumiodide (345.3 mg, 2.08 mmol). The resulting suspension was heated to 60°C. After stirring for 16 hours, the reaction mixture was cooled to roomtemperature, diluted with H₂O and extracted 3× with Et₂O. The organiclayers were combined, washed with brine, dried (Na₂SO₄) and purified bySiO₂ chromatography (EA/hexanes) to yield 6.64 g, (92.4%) of methyl6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinate (INT 31-C) asa white solid. LCMS-ESI (m/z) calculated for C₁₅H₁₁ClF₃NO₃: 345.70;found 346.1 [M+H]+, t_(R)=5.99 min. (Method 1).

Step 31-4. Synthesis of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound1-56)

A flask containing a stirred solution of INT 31-C (500 mg, 1.45 mmol) inTHE (7.23 mL) was charged with 1M NaOH (7.23 mL, 7.23 mmol). Afterstirring for 17 h at 50° C., the mixture was diluted with THF and H₂O,however no distinct layers were observed. Et₂O was added to effectseparation of the organic and aqueous layers. The aqueous layer wascollected and acidified to pH 3-4 using 3M HCl. The resulting whiteprecipitate was extracted 3× with Et₂O, and the combined organicextracts were washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to yield 310 mg (64.6%) of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)picolinic acid (Compound1-56) as a white solid. LCMS-ESI (m/z) calculated for C₁₄H₉ClF₃NO₃:331.68; found 332.1 [M+H]⁺, t_(R)=5.34 min. (Method 1).

Synthesis of Compound 31-2

Step 31-5. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT31-D)

To a solution of dimethyl pyridine-2,6-dicarboxylate (10 g, 51.2 mmol)and propanal (18.7 mL, 256.2 mmol) in H₂SO₄ (100 mL) were added FeSO₄(5.70 g, 20.49 mmol) and 30% H₂O₂ (9.9 mL, 102.5 mmol) dropwise 15 min.After stirring at 0° C. for 15 min, the mixture was diluted withsaturated K₂CO₃(aq) and extracted with EA. The organic layer was dried(Na₂SO₄), concentrated in vacuo and purified by SiO₂ chromatography(petroleum ether/EA) to afford 4.5 g (39%) of dimethyl4-ethylpyridine-2,6-dicarboxylate (INT 31-D) as a yellow solid. TLC (3:1petroleum ether:EA): R_(f)=0.6. ¹H NMR (400 MHz, CDCl₃) δ 8.13-8.20 (m,2H) 4.00-4.03 (m, 6H) 2.78-2.87 (m, 2H) 1.29-1.37 (m, 3H).

Step 31-6. Synthesis of methyl 4-ethyl-6-(hydroxymethyl)picolinate (INT31-E)

To a solution of INT-31-D (4.5 g, 20.2 mmol) in MeOH (80 mL) and DCM (20mL) was added NaBH₄ (1.14 g, 30.24 mmol) at 0° C. After stirring for 12h at 20° C., the mixture was diluted with saturated aq. NH₄Cl andextracted with EA. The organic layer was dried (Na₂SO₄), concentrated invacuo and purified by SiO₂ chromatography (petroleum ether/EA) to afford2.8 g (71%) of methyl 4-ethyl-6-(hydroxymethyl) picolinate (INT 31-E) asa yellow solid. TLC (1:1 petroleum ether:EA): R_(f)=0.4. ¹H NMR (400MHz, CDCl₃) δ 7.84-7.93 (m, 1H) 7.34-7.43 (m, 1H) 4.79-4.86 (m, 2H)3.93-4.00 (m, 3H) 2.68-2.77 (m, 2H) 1.27 (t, J=7.64 Hz, 3H).

Step 31-7. Synthesis of methyl 6-(chloromethyl)-4-ethylpicolinate (INT31-F)

To a solution of INT-31-E (2.8 g, 14.34 mmol) in DCM (100 mL) at 0° C.was added SOCl₂ (14.01 mL, 193 mmol). After 1.5 h the reaction mixturewas concentrated to provide 2.5 g (82%) of methyl6-(chloromethyl)-4-ethylpicolinate (INT-31F) as a yellow oil that wasused in the next step without any further purification. LCMS-ESI (m/z)calculated for C₁₀H₁₂ClNO₂: 213.66; found 214.0 [M+H]⁺, t_(R)=0.842 min.(Method 6).

Step 31-8. Synthesis of methyl6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate (INT31-G)

To a solution of INT-31-F (2.5 g, 11.70 mmol) and2-chloro-4-(trifluoromethyl)phenol (2.0 g, 10.18 mmol) in MeCN (160 mL)was added K₂CO₃ (4.85 g, 35.10 mmol). The suspension was stirred at 80°C. for 12 h, cooled and filtered to collect a residue that was purifiedby SiO₂ chromatography (PE:EA) to provide 4 g (82%) of methyl6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinate(INT-31-G) as a light yellow solid. TLC (3:1 petroleum ether:EA):R_(f)=0.55. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (t, J=7.58 Hz, 3H) 2.79(q, J=7.62 Hz, 2H) 4.03-4.05 (m, 3H) 5.40 (s, 2H) 7.06 (d, J=8.56 Hz,1H) 7.50 (dd, J=8.68, 1.59 Hz, 1H) 7.67-7.74 (m, 2H) 7.97 (s, 1H).

Step 31-9. Synthesis of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinic acid(Compound 31-2)

A solution of INT-31-G (3.4 g, 9.1 mmol) and LiOH—H₂O (1.15 g, 27.3mmol) in THE (5 mL) and H₂O (1 mL) was stirred at 30° C. for 12 hr. Thereaction mixture was acidified with 1N HCl to pH 6, then extracted intoEA. The combined organic extracts were dried (Na₂SO₄), concentrated anddissolved into MeCN. H₂O was added to create a white precipitate thatwas collected by filtration and washed with H₂O. The resulting filtercake was lyophilized to provide 1.93 g (58%) of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-ethylpicolinic acid(Compound 31-2) as a white solid. LCMS-ESI (m/z) calculated forC₁₆H₁₃ClF₃NO₃: 359.7; found 360.0 [M+H]⁺, t_(R)=0.95 min. (Method5-95AB_R_220&254.1 cm). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.07 (s, 1H) 7.76(s, 1H) 7.72 (d, J=1.88 Hz, 1H) 7.53 (dd, J=8.63, 1.63 Hz, 1H) 7.06 (d,J=8.63 Hz, 1H) 5.34 (s, 2H) 2.84 (q, J=7.63 Hz, 2H) 1.33 (t, J=7.57 Hz,3H).

Example 32 Synthesis of Compound 32-1

Step 32-1. Synthesis of methyl 3-cyano-5-methylbenzoate (INT 32-A)

Thionyl chloride (7 mL) was added to 3-(methoxycarbonyl)-5-methylbenzoicacid (1.5 g, 7.7 mmol). After stirring at reflux for 1 h, the reactionmixture was dissolved and concentrated 3 times with toluene. The residuewas dissolved in DCM (5 mL) and added to NH₄₀H (5 mL) at 0° C., giving awhite precipitate. The reaction mixture was stirred for 5 min at 0° C.H₂O and EA were added, and the mixture was filtered to give 1.40 g of awhite solid. To the filtered solid was added POCl₃ (4.7 mL) and thereaction mixture was heated at 100° C. for 1 h. The reaction mixture wascooled, concentrated in vacuo dissolved in DCM, and treated with sat.NaHCO₃. The mixture was extracted with EA (2×20 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to afford 1.15 g of crude material.The crude material was purified by SiO₂ chromatography (EA/hexanes) toafford 952 mg (70%) of methyl 3-cyano-5-methylbenzoate (INT 32-A) as awhite solid. LCMS-ESI (m/z) calculated for C₁₀H₉NO₂: 175.19; found 176.2[M+H]⁺, t_(R)=4.87 min. (Method 1). ¹H NMR (500 MHz, CDCl₃) δ 8.12 (brs, 1H), 8.07 (br s, 1H), 7.63 (br s, 1H), 3.94 (s, 3H), 2.45 (s, 3H).

Step 32-2. Synthesis of methyl 3-(bromomethyl)-5-cyanobenzoate (INT32-B)

To a stirring solution of INT 32-A (0.50 g, 2.9 mmol) in CCl₄ (10 mL)were added NBS (0.56 g, 3.1 mmol) and AIBN (94 mg, 0.57 mmol). Thereaction mixture was heated to 77° C. (reflux) for 4 h then concentratedin vacuo and purified by SiO₂ chromatography (EA/hexanes) to afford 247mg (34%) of methyl 3-(bromomethyl)-5-cyanobenzoate (INT 32-B) as a whitesolid. LCMS-ESI (m/z) calculated for C₁₀H₈BrNO₂: 254.08; m/z 255.2(M+H)⁺, t_(R)=5.05 min. (Method 1).

Step 32-3. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate (INT32-C)

To a stirred solution of INT 32-B (124 mg, 488 μmol) in MeCN (3 mL) wereadded 2-chloro-4-(trifluoromethyl)phenol (95.9 mg, 488 μmol) and K₂CO₃(87.7 mg, 634 μmol). After heating at 60° C. for 12 h, the reactionmixture was cooled to RT and diluted with H₂O (6 mL). The aqueous layerwas extracted with Et₂O (2×6 mL) and EA (6 mL), dried (Na₂SO₄), filteredthrough Celite, and concentrated in vacuo to afford 146.1 mg (81%) ofmethyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoate(INT 32-C) as a beige solid. LCMS-ESI (m/z) calculated forC₁₇H₁₁ClF₃NO₃: 369.72; found 370.0 [M+H]⁺, t_(R)=6.39 min. (Method 1).

Step 32-3. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid(Compound 32-1)

A vial containing a stirring solution of INT 32-C (146.1 mg, 395.2 μmol)in MeOH (2 mL) and THE (2 mL) was charged with solid NaOH (79 mg, 1.98mmol). After stirring at 50° C. for 12 h, the reaction mixture wasdiluted with H₂O and acidified to pH 4-5 using 3M HCl. The resultingwhite precipitate was extracted with Et₂O (3×10 mL) and EA (2×10 mL).The organic layers were combined, washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure to give a crude solid that waspurified by reversed phase HPLC (H₂O/CH₃CN). Lyophilization of thecombined pure fractions provided 82.6 mg (590%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-cyanobenzoic acid(Compound 32-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₆₉ClF₃NO₃: 355.0; found 354.0 [M−H]+, t_(R)=10.07 min. (Method 4). ¹HNMR (500 MHz, DMSO-d6) δ 13.60 (br s, 1H), 8.36 (s, 1H), 8.29 (s, 1H),8.18 (s, 1H), 7.89 (s, 1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (d, J=9.0Hz, 1H), 5.46 (s, 2H).

The compounds listed in Table 32 were made using the procedures ofScheme 32.

TABLE 32 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

32-1 10.067 355.70 354 [M—H]⁺  4

32-2 10.142 335.28 334 [M—H]⁺  4

32-3 4.42 356.58 353.95 [M—H]⁺ 12

32-4 4.4 371.70 370.01 [M—H]⁺ 12

32-5 4.3 355.70 354.01 [M—H]⁺ 12

Example 33 Synthesis of Compound 33-1

Step 33-1. Synthesis of methyl 3-((2-formylphenoxy)methyl)benzoate (INT33-A)

To a stirring solution of methyl 3-(bromomethyl) benzoate (300 mg, 1.31mmol) in MeCN (6 mL) were added 2-hydroxybenzaldehyde (160 mg, 1.31mmol) and K₂CO₃ (235 mg, 1.70 mmol). After heating at 60° C. for 18 h,the mixture was cooled to RT, diluted with H₂O (6 mL), and the aqueouslayer was extracted with Et₂O (2×6 mL) and EA (6 mL). The combinedorganic layers were dried (Na₂SO₄), filtered through Celite, andpurified by SiO₂ chromatography (EA/hexanes) to afford 315 mg (89%) ofmethyl 3-((2-formylphenoxy)methyl)benzoate (INT 33-A) as a white solid.LCMS-ESI (m/z) calculated for C₁₆H₁₄O₄: 270.1; found 271.5 (M+H)⁺,t_(R)=5.4 min. (Method 1).

Step 33-2. Synthesis of methyl3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B)

Into a stirring solution of INT 33-A (50 mg, 0.18 mmol) in DCM (2 mL)was added diethylaminosulfur trifluoride (0.12 mL, 0.92 mmol). Afterheating at 40° C. overnight, additional diethylaminosulfur trifluoride(0.12 mL, 0.92 mmol) was added and the reaction mixture was stirred at40° C. overnight. The reaction mixture was cooled to RT, diluted withH₂O, and extracted with DCM (3×5 mL). The combined organic extracts weredried (Na₂SO₄), filtered, concentrated in vacuo, and purified by SiO₂chromatography EA/hexanes) to provide 28.7 mg (53%) of methyl3-((2-(difluoromethyl)phenoxy)methyl)benzoate (INT 33-B). LCMS-ESI (m/z)calculated for C₁₆H₁₄F₂O₃: 292.28; found 273.2 (M+H)⁺, t_(R)=5.94 min.(Method 1). ¹H NMR (500 MHz, CDCl₃) δ 8.09 (s, 1H), 8.03-8.01 (m, 1H),7.65-7.63 (m, 1H), 7.60 (d, J=10 Hz, 1H), 7.48 (d, J=10.0 Hz, 1H),7.41-7.39 (m, 1H), 7.06 (t, J=10.0 Hz, 1H), 7.02 (t, J=55 Hz, 1H),6.99-6.97 (m, 1H), 5.17 (s, 2H), 3.94 (s, 3H).

Step 33-3. Synthesis of 3-((2-(difluoromethyl)phenoxy)methyl)benzoicacid (Compound 33-1)

Into a stirring solution of INT 33-B (28.7 mg, 98.2 μmol) in THE (2 mL)was added 1M NaOH (0.5 mL, 491 μmol). The reaction mixture was heated at60° C. overnight, concentrated in vacuo, diluted with 3M HCl, andextracted (EA and Et₂O). The combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo to afford 20.0 mg (73%) of3-((2-(difluoromethyl)phenoxy)methyl)benzoic acid (Compound 33-1) as awhite solid. LCMS-ESI (m/z) calculated for C₁₅H₁₂F₂O₃: 278.3; found277.2 [M−H]⁺, t_(R)=8.02 min. (Method 4). ¹H NMR (500 MHz, DMSO-d6) δ12.99 (br s, 1H), 8.05 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.73 (d, J=7.0Hz, 1H), 7.54-7.45 (n, 3H), 7.26-7.04 (n, 3H), 5.30 (s, 2H).

The compounds listed in Table 33 were made using the procedures ofScheme 33.

TABLE 33 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

33-1 8.02 278.25 277.2 [M—H]⁺ 4

33-2 8.761 278.25 277.2 [M—H]⁺ 4

33-3 9.3 312.70 311 [M—H]⁺ 4

33-4 8.8 296.25 295 [M—H]⁺ 4

Example 34 Synthesis of Compound 34-1

Step 34-1. Synthesis of methyl3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A)

A vial containing a stirring solution of2-bromo-4-(trifluoromethyl)phenol (316 mg, 1.31 mmol) in MeCN (5 mL) wascharged with methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) andK₂CO₃ (235 mg, 1.70 mmol). The resulting yellow suspension was stirredat 60° C. for 16 hours, cooled to room temperature, diluted with H₂O andextracted 3× with Et₂O. The organic layers were combined, washed withbrine, concentrated under reduced pressure, and purified by SiO₂chromatography (EA/hexanes) to yield 451 mg (88.5%) of methyl3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A) as awhite solid. LCMS-ESI (m/z) calculated for C₁₆H₁₂BrF₃O₃: 389.2; found391.0 (M+H)⁺, t_(R)=6.7 min. (Method 1).

Step 34-2. Synthesis of methyl3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT 34-B)

A 15 mL pressure tube containing a mixture of INT 34-A (300 mg, 771μmol) in toluene (4 mL) was charged with potassium phosphate (491 mg,2.31 mmol), tricyclohexylphosphine (32.4 mg, 116 μmol),cyclopropylboronic acid (132 mg, 1.54 mmol), and palladium (II) acetate(17.3 mg, 77.1 μmol). The tube was sealed, and the resulting orangesuspension was stirred at 100° C. for 13.5 hours, then cooled to roomtemperature and partitioned between Et₂O and H₂O. The aqueous layer wasback-extracted with Et₂O (2×). The organic layers were combined, washedwith brine, dried (Na₂SO₄), concentrated under reduced pressure andpurified by SiO₂ chromatography (EA/hexanes) to provide 201 mg (74%) ofmethyl 3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT34-B). LCMS-ESI (m/z) calculated for C₁₉H₁₇F₃O₃: 350.34; found 373.2(M+Na), t_(R)=6.8 min. (Method 1). ¹H NMR (500 MHz, DMSO-d6) δ 8.11 (s,1H), 7.93 (d, J=7.7 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.58 (t, J=7.7 Hz,1H), 7.49 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.15 (d,J=2.3 Hz, 1H), 5.34 (s, 2H), 3.86 (s, 3H), 2.18 (tt, J=8.5, 5.3 Hz, 1H),1.01-0.91 (m, 2H), 0.76-0.69 (m, 2H).

Step 34-3. Synthesis of3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid(Compound 34-1)

Into a stirring solution of INT 34-B (195 mg, 557 μmol) in THE (5 mL)was a solution of 1M NaOH (2.23 mL, 2.23 mmol). The solution was stirredovernight at 50° C. for 12.5 hours, concentrated under reduced pressure,dissolved in H₂O and acidified to pH 4-5 using 3M HCl. The resultingwhite precipitate was extracted 3× into Et₂O. The organic layers werecombined, washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to yield a crude product that was purified by prep HPLC(CH₃CN/H₂O containing 0.1% formic acid) to afford 66 mg (35%)3-((2-cyclopropyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid(Compound 34-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₈H₁₅F₃O₃: 336.3; found 335.2 [M−H]+, t_(R)=10.83 min. (Method 4). ¹HNMR (499 MHz, DMSO-d₆) δ 13.03 (s, 1H), 8.09 (s, 1H), 7.91 (d, J=7.8 Hz,1H), 7.74 (d, J=7.7 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.50 (dd, J=8.7,2.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 5.33 (s,2H), 2.18 (tt, J=8.5, 5.3 Hz, 1H), 0.99-0.91 (m, 2H), 0.76-0.69 (m, 2H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −59.98.

Example 35 Synthesis of Compound 35-1

Step 35-1. Synthesis of methyl3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT35-A)

Into a 48 mL pressure vessel containing a solution of2,3-dichloro-5-(trifluoromethyl)pyridine (433 mg, 2.01 mmol) in1,4-Dioxane (9 mL) were added methyl 3-(hydroxymethyl)benzoate (500 mg,3.01 mmol) and potassium tert-butoxide (338 mg, 3.01 mmol). The vesselwas sealed, the reaction mixture was heated and at 90° C. for 15.5hours, and then cooled to room temperature. The reaction mixture waspartitioned between Et₂O and H₂O. The phases were separated, and theaqueous layer was extracted with Et₂O (2×). The organic phases werecombined, washed with brine, dried (Na₂SO₄), concentrated and purifiedby SiO₂ chromatography (EA/hexanes) to yield 198 mg (28.6%) of methyl3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoate (INT35-A) as a white solid. LCMS-ESI (m/z) calculated for C₅H₁₁ClF₃NO₃:345.7; found 346.1 (M+H)⁺, t_(R)=6.6 min. (Method 1). ¹H NMR (500 MHz,DMSO-d6) δ 8.59 (dd, J=2.2, 1.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 8.09(t, J=1.8 Hz, 1H), 7.94 (dt, J=7.7, 1.5 Hz, 1H), 7.76 (dt, J=7.6, 1.5Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 5.60 (s, 2H), 3.86 (s, 3H).

Step 35-2. Synthesis of3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid(Compound 35-1)

A 20 mL vial containing a stirring solution of INT 35-A (190 mg, 550μmol) in THE (5 mL) was charged with 1M NaOH (2.20 mL, 2.20 mmol). Afterstirring for 22.5 hours at 50° C., the reaction mixture was concentratedunder reduced pressure, the resulting residue was dissolved in H₂O andacidified to pH 4-5 using 3M HCl. The resulting white precipitate wasextracted with Et₂O (3×). The organic layers were combined, washed withbrine, dried (Na₂SO₄) and concentrated under reduced pressure to yield150 mg (82.3%) of 3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)benzoic acid (Compound 35-1) as a white powder.LCMS-ESI (m/z) calculated for C₁₄H₉ClF₃NO₃: 331.7; found 333.2 (M+Na)⁺,t_(R)=10.1 min. (Method 3). ¹H NMR (500 MHz, DMSO-d6) δ 13.05 (s, 1H),8.60 (d, J=1.1 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.06 (s, 1H), 7.92 (d,J=7.8 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 5.59 (s,2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −60.02.

Example 36 Synthesis of Compound 36-1

Step 36-1. Synthesis of methyl 2-fluoro-3-((2-iodo-4trifluoromethyl)phenoxy)-methyl)benzoate (INT 36-A)

Into a solution of INT 4-A (300 mg, 1.21 mmol) and2-iodo-4-(trifluoromethyl)phenol (349.72 mg, 1.21 mmol) in CH₃CN (10 mL)was added K₂C₃ (218.17 mg, 1.58 mmol). After stirring at 60° C. for 12h, the reaction mixture was filtered and the filtrate was concentratedto provide 500 mg (91%) of methyl2-fluoro-3-((2-iodo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT36-A)that was used without further purification. LCMS-ESI (m/z) calculatedfor C₁₆H₁₁F₄IO₃: 454.16; found 454.9 (M+H)⁺, t_(R)=1.04 min. (Method 6).

Step 36-2. Synthesis of methyl2-fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenoxy)methyl)benzoate (INT 36-B)

Into a solution of INT 36-A (500 mg, 1.10 mmol) in THE (10 mL) wereadded ethynyl(trimethyl)silane (167.7 μL, 1.21 mmol), dichloropalladiumtriphenyl phosphine (77.28 mg, 110.09 μmol), CuI (20.97 mg, 110.09 μmol)and TEA (459.72 μL, 3.30 mmol). After stirring at 40° C. 12 h, themixture was poured into H₂O (20 mL) and extracted with EA (3×20 mL). Theorganic layer was dried (Na₂SO₄), concentrated, and purified by SiO₂chromatography (PE, EA) to provide 200 mg (42%) of methyl2-fluoro-3-((4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenoxy)methyl)benzoate (INT 36-B) as a white solid. TLC (5:1PE:EA, R_(f)=0.7)¹H NMR (400 MHz, CDCl₃) δ 7.95-7.90 (m, 2H), 7.74 (s,1H), 7.57-7.53 (m, 1H), 7.33-7.27 (m, 1H), 7.05-7.01 (m, 1H), 5.29 (s,2H), 3.96 (s, 3H), 0.31-0.27 (m, 9H).

Step 36-3. Synthesis of3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(Compound 36-1)

Into a suspension of INT 36-B (185 mg, 0.44 mmol) in MeOH (5 mL) and H₂O(5 mL), and THE (5 mL) was added NaOH (52.3 mg, 1.4 mmol). Afterstirring at 30° C. for 1.5 h, the reaction mixture was concentrated,dissolved in MeOH (5 mL), filtered and purified by prep-HPLC (H₂O/CH₃CNwith formic acid) to provide 59 mg (48%) of3-((2-ethynyl-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoic acid(Compound 36-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₇H₁₀F₄O₃: 338.3; found 339.1 (M+Na)+, t_(R)=0.786 min. (Method 6). ¹HNMR (400 MHz, DMSO-d6) δ ppm 4.44 (s, 1H) 5.38 (s, 2H) 7.36 (t, J=7.69Hz, 1H) 7.43 (d, J=8.50 Hz, 1H) 7.75-7.84 (m, 3H) 7.88 (td, J=7.38, 1.75Hz, 1H).

Example 37 Synthesis of Compound 37-1

Step 37-1. Synthesis of methyl 3-(hydroxymethyl)-2-vinylbenzoate (INT37-A)

To a suspension of dimethyl 2-bromobenzene-1,3-dicarboxylate (1 g, 3.66mmol) and Na₂CO₃ (776.25 mg, 7.32 mmol) in 1,4-dioxane (20 mL) and H₂O(4 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (683.25μL, 4.03 mmol). The reaction mixture was treated with Pd(dppf)Cl₂—CH₂Cl₂(149.5 mg, 183.1 μmol) and stirred at 100° C. for 12 hr. The mixture wasfiltered. The filtrate was partitioned between EA (30 ml) and H₂O (30ml). The aqueous layer was back-extracted with EA (30 ml). The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated undervacuum to provide a residue that was purified by SiO₂ chromatography toprovide 680 mg (84.3%) of methyl 3-(hydroxymethyl)-2-vinylbenzoate (INT37-A) as a colorless oil. TLC (5:1 PE:EA): R_(f)-0.7.

Step 37-2. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT37-B)

H₂ (15 psi) was bubbled into a solution of INT 37-A (680 mg, 3.09 mmol),Pd/C (70 mg, 308.8 umol, 10% purity) in MeOH (10 mL) at 30° C. for 12hr. The reaction mixture was filtered and the filtrate was concentratedto give a crude product that was purified by SiO₂ chromatography (EA/PE)to provide 560 mg (81.6%) of methyl 2-ethyl-3-(hydroxymethyl)benzoate(INT 37-B) as a colorless oil. TLC (5:1 PE:EA): R_(f)=0.4. ¹H NMR (400MHz, CDCl₃) δ ppm 1.25 (t, J=7.40 Hz, 3H) 3.15 (q, J=7.46 Hz, 2H) 3.92(s, 6H) 7.30 (t, J=7.76 Hz, 1H) 7.85 (d, J=7.70 Hz, 2H).

Step 37-3. Synthesis of methyl 2-ethyl-3-(hydroxymethyl)benzoate (INT37-C)

Into a solution of INT 37-B (0.4 g, 1.80 mmol) in THE (10 mL) at 0° C.were added NaBH₄ (102.13 mg, 2.70 mmol) and MeOH (2 mL). After stirring12 h at 70° C., the mixture was poured into saturated NH₄Cl (aq. 20 mL)and extracted with EA (3×20 mL). The combined organic layers were dried(Na₂SO₄), concentrated, and purified by prep-TLC to provide 170 mg(48.6%) of methyl 2-ethyl-3-(hydroxymethyl) benzoate (INT 37-C) as ayellow oil. TLC (5:1 PE:EA): R_(f)=0.5.

Step 37-4. Synthesis of methyl 3-(chloromethyl)-2-ethylbenzoate (INT37-D)

Into a solution of INT 37-C (70 mg, 360.4 μmol) in DCM (2 mL) was addedSOCl₂ (130.7 μL, 1.80 mmol) at 0° C. After stirring at 30° C. for 1 h,the reaction mixture was concentrated in vacuo to provide 72 mg (94%) ofmethyl 3-(chloromethyl)-2-ethyl-benzoate (INT 37-D) as brown gum thatwas used in the next step without further purification. TLC (5:1 PE:EA):R_(f)=0.7.

Step 37-5. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoate (INT37-E)

Into a suspension of INT 37-D (70 mg, 329.15 μmol) and K₂CO₃ (136.47 mg,987.44 μmol) in CH₃CN (2 mL) was added2-chloro-4-(trifluoromethyl)phenol (71.16 mg, 362.06 μmol, 1.1 eq).After stirring at 80° C. for 12 h the reaction mixture was filtered andthe filtrate was concentrated in vacuo to provide a residue that waspurified by SiO₂ chromatography (EA/PE) to provide 59 mg (48%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethyl-benzoate (INT37-E) as a light yellow gum. TLC (10:1 PE:EA): R_(f)=0.75. LCMS-ESI(m/z) calculated for C₁₈H₁₆ClF₃O₃: 372.7; found 373.4 (M+H)⁺, t_(R)=1.14min. (Method 6). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, J=1.3, 7.8 Hz, 1H),7.66-7.63 (m, 1H), 7.62 (s, 1H), 7.46 (dd, J=1.6, 8.7 Hz, 1H), 7.30-7.22(m, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.22 (s, 2H), 3.89 (s, 3H), 2.97 (q,J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).

Step 37-6. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid(Compound 37-1)

Into a solution of INT 37-E (156 mg, 418.5 umol) in THE (3 mL), MeOH (1mL) and H₂O (1 mL) was add NaOH (42.92 mg, 1.07 mmol). After stirring at50° C. for 12 h, the mixture was acidified with 3M hydrochloride acidthen partitioned between EA (10 ml) and H₂O (10 ml). The organic layerwas dried (Na₂SO₄) filtered and concentrated in vacuo. The resultingresidue was purified by prep-HPLC (H₂O (0.225% FA)—CH₃CN) to provide 144mg (77%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-ethylbenzoic acid(Compound 37-1). LCMS-ESI (m/z) calculated for C₁₇H₁₄ClF₃O₃: 358.7;found 357.0 (M−H)+, t_(R)=0.95 min. (Method 8). ¹H NMR (400 MHz, CDCl₃)δ 8.02 (dd, J=1.1, 7.8 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.69 (d, J=2.1Hz, 1H), 7.52 (dd, J=1.7, 8.7 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.09 (d,J=8.6 Hz, 1H), 5.28 (s, 2H), 3.12 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.5 Hz,3H

Example 38 Synthesis of Compound 38-1

Step 38-1 Synthesis of methyl3-((tert-butoxycarbonyl)amino)-5-methylbenzoate (INT 38-A)

Into a solution of methyl 3-amino-5-methyl-benzoate (1 g, 6.05 mmol, 1),di-tert-butyl dicarbonate (2.64 g, 12.11 mmol) and TEA (1.69 mL, 12.11mmol) in CH₃CN (15 mL) was added 4-dimethylamino pyridine (73.96 mg,605.37 μmol). The reaction mixture was stirred at 50° C. for 12 h thenfiltered. The filtrate was concentrated and the residue was purified bySiO₂ chromatography (EA/PE) to provide 850 mg (53%) of methyl3-((tert-butoxycarbonyl)amino)-5-methylbenzoate (INT 38-A) as a yellowgum. TLC (5:1 PE:EA): R_(f)=0.7. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s,9H) 2.40 (s, 3H) 3.91 (s, 3H) 7.28 (s, 1H) 7.75 (s, 1H) 7.82 (s, 1H).

Step 38-2 Synthesis of methyl3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B)

Into a solution of INT 38-A (750 mg, 2.83 mmol) and NBS (604 mg, 3.39mmol) in CCl₄ (10 mL) was added AIBN (46 mg, 282 μmol). After stirringat 80° C. for 12 h, the reaction mixture was filtered purified by SiO₂chromatography (EA/PE) to provide 800 mg (82%) of methyl3-(bromomethyl)-5-((tert-butoxycarbonyl)amino)benzoate (INT 38-B) as abrown gum. TLC (10:1 PE:EA): R_(f)=0.45.

Step 38-3 Synthesis of methyl3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate(INT 38-C)

Into a suspension of INT 38-B (560 mg, 1.63 mmol) and K₂CO₃ (674.57 mg,4.88 mmol) in CH₃CN (10 mL) was added 2-chloro-4-(trifluoromethyl)phenol(351.76 mg, 1.79 mmol). After stirring at 80° C. for 12 h, the reactionmixture was filtered, concentrated, and purified by SiO₂ chromatographyto provide 140 mg (18%) of methyl3-((tert-butoxycarbonyl)amino)-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate(INT 38-C) as alight yellow gum. TLC (10:1 PE:EA): R_(f)=0.60. LCMS-ESI(m/z) calculated for C₂₁H₂₁ClF₃NO₅: 459.85; found 458 (M−H)+, t_(R)=1.12min (Method 6). ¹H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.15 (s, 1H),7.87 (d, J=1.9 Hz, 1H), 7.78 (s, 1H), 7.72-7.68 (m, 2H), 7.39 (d, J=8.9Hz, 1H), 5.35 (s, 2H), 3.85 (s, 3H), 1.48 (s, 9H).

Step 38-4 Synthesis of methyl3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT38-D)

A solution of INT 38-C (60 mg, 130.48 μmol) in HCl/dioxane (4 M, 1 mL)was stirred at 30° C. for 1 hr. The reaction mixture was concentrated invacuo to give 55 mg of crude methyl3-amino-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT38-D) as a gray solid that was used into the next step without furtherpurification. TLC (10:1 PE:EA): R_(f)=0.65.

Step 38-5 Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate(INT 38-E)

Into a suspension of INT 38-D (50 mg, 138.99 μmol) and K₂CO₃ (38.42 mg,278 umol) in MECN (3 mL) was added MeI (17.31 uL, 277.99 umol). Thereaction mixture was stirred at 30° C. for 12 h, filtered and purifiedby SiO₂ chromatography to provide 12 mg (22%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoate(INT 38-E) as a light yellow gum. TLC (5:1 PE:EA): R_(f)=0.8. LCMS-ESI(m/z) calculated for C₁₈H₁₇ClF₃NO₃: 387.8; found 388 (M−H)+, t_(R)=0.99min (Method 6). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.66 (d, J=1.88 Hz, 1H)7.46 (dd, J=8.63, 1.63 Hz, 1H) 7.42 (s, 1H) 7.36 (s, 1H) 7.00-7.06 (m,2H) 5.21 (s, 2H) 3.92 (s, 3H) 3.02 (s, 6H).

Step 38-6 Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoic acid (Compound 38-1)

To a solution of INT 38-E (12 mg, 30.95 μmol) in THE (1 mL), MeOH (0.5mL) and H₂O (0.5 mL) was added NaOH (4.95 mg, 123.78 μmol). Afterstirring at 50° C. for 4 h, the mixture was acidified with 3Mhydrochloride acid. The mixture was partitioned between EA (10 ml) andH₂O (10 ml) and the resulting organic layer was dried (Na₂SO₄),filtered, and purified by prep-HPLC (H₂O (0.225% FA)—CH₃CN) to provide3.6 mg (31%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(dimethylamino)benzoicacid (Compound 38-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₇H₁₅ClF₃NO₃: 373.76; found 374.1 (M+H)⁺, t_(R)=0.93 min (Method 6). ¹HNMR (400 MHz, CDCl₃) δ 7.67 (d, J=1.8 Hz, 1H), 7.50-7.44 (m, 2H), 7.41(s, 1H), 7.09-7.02 (m, 2H), 5.23 (s, 2H), 3.03 (s, 6H).

Example 39 Synthesis of Compound 39-1

Step 39-1. Synthesis of 4-allyl-2,6-dichloropyridine (INT 39-A)

Into a mixture of ^(i)PrMgCl—LiCl (1 M, 12.78 mL) in THE (100 mL) at−60° C. was added 2,6-dichloro-4-iodopyridine (2.8 g, 10.22 mmol). Themixture was stirred at −60° C. for 0.5 h, then 3-bromoprop-1-ene (1.55g, 12.78 mmol) and CuCN (1.14 g, 12.78 mmol) were added and the mixturewas stirred for 16 h at 25° C. The reaction mixture was quenched by theaddition of H₂O (100 mL) and extracted with EA (3×50 mL). The combinedorganic layers were dried and concentrated to give a residue that waspurified by prep-TLC (PE) to provide 1.4 g (73%) of4-allyl-2,6-dichloropyridine (INT 39-A) as a yellow oil. TLC (PE):R_(f)=0.50.

Step 39-2. Synthesis of dimethyl 4-allylpyridine-2,6-dicarboxylate (INT39-B)

Into a solution of INT 39-A (1.4 g, 7.44 mmol) Pd(dppf)Cl₂—CH₂Cl₂ (3.04g, 3.72 mmol) and TEA (6.22 mL, 44.67 mmol) in MeOH (10 mL) was bubbledCO gas (20.85 g, 744.47 mmol). The mixture was stirred at 70° C. for 12h then filtered. The resulting residue was purified by SiO₂chromatography (EA/PE) to provide 1.75 g (60%) of dimethyl4-allylpyridine-2,6-dicarboxylate (INT 39-B) as a black solid. TLC (1:1EA:PE): R_(f)=0.50.

Step 39-3. Synthesis of dimethyl 4-propylpyridine-2,6-dicarboxylate (INT39-C)

A solution of INT 39-B (2.9 g, 12.33 mmol) and Pd/C (0.3 g, 1.23 mmol,10% purity) in MeOH (80 mL) was stirred at 25° C. for 12 h under H₂ (50psi). The reaction mixture was filtered and concentrated to give aresidue that was purified by SiO₂ chromatography (EA) to provide 2.5 g(85%) of dimethyl 4-propylpyridine-2,6-dicarboxylate (INT 39-C) as ayellow solid. TLC (1:1 EA:PE): R_(f)=0.80. ¹H NMR (400 MHz, CDCl₃) δ ppm8.14 (s, 2H) 4.02 (s, 6H) 2.76 (t, J=7.64 Hz, 2H) 1.75 (sxt, J=7.46 Hz,2H) 0.98 (t, J=7.34 Hz, 3H).

Step 39-4. Synthesis of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-propylpicolinic acid(Compound 39-1)

The synthesis of Compound 39-1 was completed from INT 39-C asdemonstrated in Scheme 31. LCMS-ESI (m/z) calculated for C₁₇H₁₅ClF₃NO₃:373.76; found 373.8 (M+H)⁺, t_(R)=0.786 min. (Method 6). ¹H NMR (400MHz, DMSO-d6) δ 7.85-7.91 (m, 2H) 7.71 (dd, J=8.76, 1.63 Hz, 1H) 7.61(s, 1H) 7.45 (d, J=8.63 Hz, 1H), 5.42 (s, 2H) 2.70 (t, J=7.50 Hz, 2H)1.62 (m, J=7.40 Hz, 2H) 0.87 (t, J=7.32 Hz, 3H).

Example 40 Synthesis of Compound 40-1

Step 40-1. Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonamide (INT 40-A)

To a solution of 3-(bromomethyl) benzenesulfonamide (100 mg, 400 μmol)in CH₃CN (3 mL) were added 2-chloro-4-(trifluoromethyl)phenol (78.6 mg,400 μmol) and K₂CO₃ (111 mg, 800 μmol). After stirring at 30° C. for 12h, the mixture was concentrated to give a crude product that waspurified by prep-HPLC (H₂O (0.225% FA)/CH₃CN) to provide 70 mg (48%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzenesulfonamide (INT40-A) as a white solid. LCMS-ESI (m/z) calculated for C₁₄H₁₁ClF₃NO₃S:365.8; found 364.0 (M−H)+, t_(R)=0.967 min. (Method 7).

Step 40-2. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzenesulfonic acid(Compound 40-1)

To a solution of INT 40-A (30 mg, 82 μmol) in THE (3 mL) were added HCl(2 M, 41.01 μL) and NaNO₂ (9.6 mg, 139 μmol). After stirring at 40° C.for 12 h, the mixture was concentrated to give a crude product that waspurified by prep-HPLC (H₂O (0.1% TFA)/CH₃CN) to provide 2.6 mg (8.5%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzenesulfonic acid(Compound 40-1) as brown gum. LCMS-ESI (m/z) calculated forC₁₄H₁₀ClF₃O₄S: 366.7; found 365.0 (M−H)+, t_(R)=0.708 min. (Method 7).

Example 41 Synthesis of Compound 41-1

Step 41-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT41-A)

To a solution of 2,6-dichloro-4-methyl-pyridine (1 g, 6.17 mmol) in DMF(20 mL) and MeOH (10 mL) were added Pd(dppf)Cl₂—CH₂Cl₂ (504.05 mg,617.22 μmol) and TEA (3.44 mL, 24.69 mmol). After stirring at 80° C.under an atmosphere of CO (50 PSI) for 16 h, the reaction mixture wasfiltered, concentrated, diluted with H₂O and extracted with EA (2×50mL). The combined organic layers were dried (Na₂SO₄), filtered,concentrated, and purified by SiO₂ chromatography (EA/PE) to provide 900mg (68%) of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT 41-A) as ayellow solid. TLC (2:1 EA:PE): R_(f)=0.20. LCMS-ESI (m/z) calculated forC₁₀H₁₁NO₄: 209.2; found 210.6 (M+H)⁺, t_(R)=0.756 min. (Method 7). ¹HNMR (400 MHz, DMSO-d6) δ 8.12 (d, J=0.7 Hz, 2H), 3.91 (s, 6H), 2.49-2.48(s, 3H).

Step 41-2. Synthesis of 4-methyl-6-((naphthalen-2-yloxy)methyl)picolinicacid (Compound 41-1)

4-methyl-6-((naphthalen-2-yloxy)methyl)picolinic acid (Compound 41-1)was synthesized following Scheme 31 (Steps i-iv) from INT 41-A andnaphthalen-2-ol, obtained as a white solid. LCMS-ESI (m/z) calculatedfor C₁₈H₁₅NO₃: 293.3; found 294.2 (M+H)⁺, t_(R)=0.789 min. (Method 7).¹H NMR (400 MHz, DMSO-d6) δ 12.93-13.50 (m, 1H) 7.77-7.90 (m, 4H) 7.64(s, 1H) 7.42-7.50 (m, 2H) 7.33-7.40 (m, 1H) 7.30 (dd, J=8.94, 2.44 Hz,1H) 5.22-5.41 (m, 2H) 2.38-2.45 (m, 3H).

The compounds listed in Table 41 were made using the procedures ofScheme 41.

TABLE 41 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

41-1 0.715 293.32 293.9 [M + H]⁺ 6

41-2 0.913 345.70 346 [M + H]⁺ 6

Example 42 Synthesis of Compound 42-1

Step 42-1. Synthesis of dimethyl 4-ethylpyridine-2,6-dicarboxylate (INT42-A)

To a solution of dimethyl pyridine-2,6-dicarboxylate (10 g, 51.2 mmol)and propanal (18.65 mL, 256.2 mmol) in H₂SO₄ (100 mL) were added FeSO₄(5.70 g, 20.49 mmol) and 30% H₂O₂ (9.85 mL, 102.47 mmol) dropwise over15 min. After stirring at 0° C. for 15 min, the mixture was diluted withsaturated K₂CO₃(aq) and extracted with EA (3×200 mL). The combinedorganic layers were dried (Na₂SO₄), concentrated, purified by SiO₂chromatography (EA/PE) to provide 4.5 g (39%) of dimethyl4-ethylpyridine-2,6-dicarboxylate (INT 42-A) as a yellow solid. TLC (3:1EA:PE): R_(f)=0.60. ¹H NMR (400 MHz, CDCl₃) δ 8.13-8.20 (m, 2H)4.00-4.03 (m, 6H) 2.78-2.87 (m, 2H) 1.29-1.37 (m, 3H).

Step 42-2. Synthesis of 4-ethyl-6-((naphthalen-2-yloxy)methyl)picolinicacid (Compound 42-1)

4-ethyl-6-((naphthalen-2-yloxy) methyl) picolinic acid (Compound 42-1)was synthesized following Scheme 31 (Steps i-iv) from INT 42-A andnaphthalen-2-ol, and was obtained as a light yellow solid. LCMS-ESI(m/z) calculated for C₁₉H₁₇NO₃: 307.4; found 307.9 (M+H)⁺, t_(R)=0.743min. (Method 6). ¹H NMR (400 MHz, DMSO-d6) δ 12.82-13.61 (m, 1H)7.78-7.91 (m, 4H) 7.68 (s, 1H) 7.43-7.50 (m, 2H) 7.33-7.39 (m, 1H) 7.31(dd, J=8.88, 2.50 Hz, 1H) 5.26-5.41 (m, 2H) 2.74 (q, J=7.63 Hz, 2H)1.13-1.30 (m, 3H).

The compounds listed in Table 42 were made using the procedures ofScheme 42.

TABLE 42 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

42-1 0.754 307.35 307.9 [M + H]⁺ 6

42-2 0.828 360.62 359.8 [M—H]⁺ 6

42-3 1.007 359.73 360.2 [M + H]⁺ 6

Example 43 Synthesis of Compound 43-1

Step 43-1. Synthesis of dimethyl 4-bromopyridine-2,6-dicarboxylate (INT43-A)

PBr₃ (1.61 mL, 16.9 mmol) was added to a solution of Br₂ (700 μL, 13.7mmol) in hexanes (10.0 mL) at 0° C. The mixture was stirred at 22° C.for 1 h. 4-Hydroxypyridine-2,6-dicarboxylic acid (1.00 g, 5.46 mmol) wasadded, and the mixture was stirred at 90° C. for 6 h. The mixture wascooled and diluted with CHCl₃ (50 mL). Anhydrous MeOH (50 mL) was addeddropwise at 0° C., and the mixture was stirred at 22° C. for 1 h. Themixture was concentrated, and the residue was dissolved in DCM (50 mL)and diluted with sat. aq. NaHCO₃ (50 mL). The aq. phase was extractedwith DCM (4×50 mL), and the combined organic layers were dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by SiO₂ chromatography (EA/hexanes) to provide 924 mg (62%) ofdimethyl 4-bromopyridine-2,6-dicarboxylate (INT 43-A) as a solid.LCMS-ESI (m/z) calculated for C₉H₈BrNO₄: 274.07; found 276.1 (M+H)⁺,t_(R)=2.04 min. (Method 13).

Step 43-2. Synthesis of methyl4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT 43-B)

NaBH₄ (191 mg, 5.06 mmol) was added to a solution of INT 43-A (924 mg,3.37 mmol) in MeOH and DCM (4:1 v/v, 50 mL) at 0° C. The mixture wasstirred at 0° C. for 30 min. Saturated aq. NaHCO₃ (50 mL) was added, andthe aq. phase was extracted with DCM (4×30 mL). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated to provide 690 mg(83%) of methyl 4-bromo-6-(hydroxymethyl)pyridine-2-carboxylate (INT43-B) as a solid. LCMS-ESI (m/z) calculated for C₈H₈BrNO₃: 246.06; found246.1 (M+H)⁺, t_(R)=1.78 min. (Method 13).

Step 43-3. Synthesis of methyl4-bromo-6-(bromomethyl)pyridine-2-carboxylate (INT 43-C)

PBr₃ (450 μL, 4.74 mmol) was added to a solution of INT 43-B (690 mg,2.80 mmol) in CHCl₃ (35.0 mL) at 0° C. The mixture was stirred at 22° C.for 5 h, cooled to 0° C., and diluted with sat. aq. K₂CO₃ (25.0 mL). Theaq. phase was extracted with EA (3×30 mL), and the combined organiclayers were washed with brine (20 mL), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by SiO₂ chromatography(EA/hexanes) to provide 700 mg (81%) of dimethyl4-bromopyridine-2,6-dicarboxylate (INT 43-C) as a solid. LCMS-ESI (m/z)calculated for C₈H₇Br₂NO₂: 308.96; found 246.1 (M+H)⁺, t_(R)=2.22 min.(Method 13).

Step 43-4. Synthesis of methyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-D)

2-Chloro-4-(trifluoromethyl)phenol (490 mg, 2.49 mmol) and Cs₂CO₃ (1.48g, 4.53 mmol) were added to a solution of INT 43-C (700 mg, 2.27 mmol)in anhydrous DMF (5 mL) at 22° C. The mixture was stirred at 50° C. for18 h, cooled to rt, and diluted with H₂O (25 mL). The aq. phase wasextracted with EA (3×30 mL), and the combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by SiO₂ chromatography (EA/hexanes) to provide 750mg (78%) of methyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate(INT 43-D) as a solid. LCMS-ESI (m/z) calculated for C₁₅H₁₀BrClF₃NO₃:422.95; found 424.4 (M+H)⁺, t_(R)=2.78 min. (Method 13).

Step 43-5. Synthesis of methyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate (INT 43-E)

Zn(CN)₂ (59.7 mg, 0.509 mmol) and Pd(PPh₃)₄ (44.1 mg, 0.038 mmol) wereadded to a solution of INT 43-D (108 mg, 0.254 mmol) in degassed DMF(2.00 mL) at 22° C. The mixture was purged with N₂ for 5 min and stirredat 150° C. for 6 h. The mixture was concentrated, and the residue waspurified by SiO₂ chromatography (EA/hexanes) to provide 74 mg (79%) ofmethyl4-bromo-6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)pyridine-2-carboxylate(INT 43-E) as a solid. LCMS-ESI (m/z) calculated for C₁₆H₁₀ClF₃N₂O₃:370.03; m/z not observed)⁺, t_(R)=2.78 min. (Method 13).

Step 43-6. Synthesis of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylicacid (Compound 43-1)

Aqueous 2 M NaOH (299 μL 0.150 mmol) was added to a solution of INT 43-E(74.0 mg, 0.20 mmol) in MeOH (1 mL) and THE (1 mL) at 22° C. The mixturewas stirred at 22° C. for 2 h and concentrated. The residue wasacidified with aq. 2 M HCl (pH 2) and diluted with H₂O (10 mL). The aq.phase was extracted with EA (3×10 mL), and the combined organic layerswere washed with brine (10 mL), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by reverse phase chromatography(H₂O (+0.1% formic acid)/CH₃CN) to provide 63 mg (89%) of6-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-4-cyano-pyridine-2-carboxylic acid (Compound 43-1) as a solid.LCMS-ESI (m/z) calculated for C₁₅H₈ClF₃N₂O₃: 356.7; found 357.1 (M+H)⁺,t_(R)=3.91 min. (Method 12). ¹H NMR (500 MHz, DMSO-d6) δ 13.84 (br s,1H), 8.39 (d, J=1.4 Hz, 1H), 8.17 (d, J=1.4 Hz, 1H), 7.92 (d, J=2.2 Hz,1H), 7.73 (dd, J=2.3, 8.7 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 5.51 (s, 2H).

Example 44 Synthesis of Compound 44-1

Step 44-1. Synthesis of methyl3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzoate (INT44-A)

A mixture of methyl 3-bromo-5-(bromomethyl)benzoate (3.60 g, 11.7 mmol),2-chloro-4-(trifluoromethyl)phenol (1.48 mL, 11.1 mmol) and K₂CO₃ (4.85g, 35.1 mmol) in acetone (30 mL) was stirred at 90° C. for 1 h. Themixture was filtered, and the filtrate was concentrated. The residue waspurified by SiO₂ chromatography (EA/hexanes) to provide 2.36 g (48%) ofmethyl 3-bromo-5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoate(INT 44-A) as a solid. LCMS-ESI (m/z) calculated for C₁₆H₁₁BrClF₃O₃:423.61; found 442.2 (M+H₂O), t_(R)=3.29 min (Method 13). ¹H NMR (400MHz, CDCl₃) δ 8.18-8.13 (m, 1H), 8.05 (tt, J=1.5, 0.7 Hz, 1H), 7.84 (td,J=1.7, 0.8 Hz, 1H), 7.68 (dt, J=2.3, 0.7 Hz, 1H), 7.52-7.45 (m, 1H),7.06-6.94 (m, 1H), 5.20 (s, 2H), 3.94 (s, 3H).

Step 44-2. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate(INT 44-B)

A mixture of INT 44-A (150 mg, 0.354 mmol), 2-methyloxazole (58.0 μL,0.708 mmol), Pd(PPh₃)₄ (41.0 mg, 0.035 mmol), and KOAc (70.0 mg, 0.708mmol) in DMF (4.00 mL) was stirred at 110° C. for 16 h. The mixture wascooled and diluted with H₂O (20 mL). The aq. phase was extracted with EA(3×20.0 mL), and the combined organic layers were washed with brine (20mL), dried (MgSO₄), filtered, and concentrated. The residue was purifiedby SiO₂ chromatography (EA/hexanes) to provide 98 mg (65%) of methyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoate(INT 44-B) as a solid. LCMS-ESI (m/z) calculated for C₂₀H₁₅ClF₃NO₄:425.06; found 426.25 (M+H)⁺, t_(R)=2.79 min (Method 13). ¹H NMR (500MHz, CDCl₃) δ 8.25 (t, J=1.6 Hz, 1H), 8.07-8.03 (m, 1H), 7.95-7.89 (m,1H), 7.71-7.65 (m, 1H), 7.49 (ddd, J=8.7, 2.3, 0.8 Hz, 1H), 7.33 (s,1H), 7.08-7.00 (m, 1H), 5.26 (s, 2H), 3.97 (s, 3H), 2.56 (s, 3H).

Step 44-3. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoicacid (Compound 44-1)

A solution of NaOH (1 M in H₂O, 676 μL, 0.676 mmol) was added to amixture of INT 44-B (96.0 mg, 0.225 mmol) in THE and H₂O (3:1 v/v, 4.00mL). The mixture was stirred at 22° C. for 4 h. The mixture wasacidified with aq. 1 M HCl (pH 2) and diluted with EA (20 mL). The aq.phase was extracted with EA (2×30 mL), and the combined organic layerswere washed with brine (20 mL), dried (MgSO₄), filtered, andconcentrated. The residue was purified by SiO₂ chromatography (MeOH/DCM)to provide 77.5 mg (83%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(2-methyloxazol-5-yl)benzoic acid (Compound 44-1) as a solid. LCMS-ESI (m/z) calculated forC₁₉H₁₃ClF₃NO₄: 411.05; found 412.2 (M+H)⁺, t_(R)=4.59 min (Method 12).¹H NMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.17 (dd, J=1.7 Hz, 1H),8.04-7.98 (m, 2H), 7.88 (d, J=2.3 Hz, 1H), 7.73 (dd, J=8.9, 2.3 Hz, 1H),7.66 (s, 1H), 7.45 (d, J=8.7 Hz, 1H), 5.43 (s, 2H), 2.50 (s, 3H).

Example 45 Synthesis of Compounds 45-1 and 45-2

Step 45-1. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound 45-1)

Into a solution of 3-(bromomethyl) benzamide (254 mg, 1.29 mmol) in DMF(5 mL) at 0° C. was added NaH. After the reaction mixture was stirredand allowed to warm to RT over 30 min,2-chloro-4-(trifluoromethyl)phenol (250 mg, 1.17 mmol) was added. After4 h, the reaction mixture was diluted with EA and washed with H₂O, 1 MHCl, 1 M NaOH, H₂O, brine, dried (Na₂SO₄), filtered and concentrated.The resulting crude residue was purified by reverse phase SiO₂chromatography (MeOH/H₂O) to provide material that was triturated withMeOH/H₂O, filtered, and dried in vacuo to provide 260 mg (67%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound45-1). LCMS-ESI (m/z) calculated for C₅H₁₁ClF₃NO₂: 329.04; found 330.1(M+H)⁺, t_(R)=12.14 min (Method 10). ¹H NMR (300 MHz, CDCl₃) δ 7.96 (s,1H), 7.80 (d, J=7.7 Hz, 1H), 7.69 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.54(d, J=7.7 Hz, 1H), 7.51 (d, J=6.6 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.11(bs, 1H), 5.69 (bs, 1H), 5.28 (s, 2H).

Step 45-2. Synthesis of3-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-1,2,4-triazole(Compound 45-2)

A solution of Compound 45-1 (260 mg, 0.079 mmol) in dimethylformamidedimethyl acetal (4 mL) was heated at 120° C. for 2 h. The reactionmixture was cooled to RT and concentrated in vacuo. The resultingresidue was dissolved in AcOH (4 mL) and N₂H₄—H₂O (47 mg, 0.946 mmol)was added dropwise. After stirring at 90° C. for 2 h, the mixture wasconcentrated, diluted with Et₂O and cooled to 0° C. The resultingprecipitate was collected by filtration and purified by SiO₂chromatography (EA/hexane) to provide 125 mg (45%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzamide (Compound45-2). LCMS-ESI (m/z) calculated for C₁₆H₁₁ClF₃N₃O: 353.05; found 354.5(M+H)⁺, t_(R)=13.56 min (Method 10). ¹H NMR (300 MHz, CDCl₃) δ 8.30 (s,1H), 8.16 (s, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H),7.56-7.44 (m, 3H), 7.03 (d, J=8.6 Hz, 1H), 5.24 (s, 2H).

The compounds listed in Table 45 were made using the procedures ofScheme 45.

TABLE 45 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

45-1 13.13 329.70 330.1 [M + H]⁺ 10

45-2 13.56 353.73 354.5 [M + H]⁺ 10

Example 46 Synthesis of Compound 46-1

Step 46-1. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide (INT 46-A)

Into a solution of Compound 1-29 (500 mg, 1.51 mmol) in DMF (10 mL) wereadded N,O-dimethylhydroxylamine hydrochloride (161 mg, 1.66 mmol), HATU(632 mg, 1.66 mmol), and DIPEA (585 mg, 4.5 mmol). After the reactionmixture was stirred for 18 h, the reaction mixture was acidified withTFA and purified by reverse phase SiO₂ chromatography (MeOH/H₂O, 0/1%TFA) to provide 530 mg (94%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-methoxy-N-methylbenzamide(INT 46-A). LCMS-ESI (m/z) calculated for C₁₇H₁₅ClF₃NO₃: 373.07; m/z notobserved; t_(R)=6.2 min (Method 11).

Step 46-2. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B)

Into a solution of INT 46-A (1000 mg, 2.68 mmol) in THE (10 mL) at −78°C. was added DIBAL (3.21 mL of 1M/THF solution, 3.21 mmol). After thereaction mixture was stirred for 30 min, H₂O was added and the solutionwas extracted EA, dried (Na₂SO₄), and purified by SiO₂ chromatography(EA/hexanes) to provide 600 mg (71.1%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzaldehyde (INT 46-B).LCMS-ESI (m/z) calculated for C₁₅H₁₀ClF₃O₂. 314.03; m/z not observed,t_(R)=6.3 min (Method 11).

Step 46-3. Synthesis of2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole(Compound 46-1)

Into a solution of INT 46-B (100 mg, 0.32 mmol) in EtOH (5 mL) at 0° C.were added oxalaldehyde (0.04 mL of 8.8 M/H₂O solution, 0.35 mmol) andNH₄OH (0.053 mL of 29% solution in EtOH, 0.44 mmol). After stirring for48 h, the mixture was concentrated and purified by SiO₂ chromatography(EA/hexanes) to provide 40 mg (35%) of2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole(Compound 46-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₇H₁₂ClF₃N₂O. 352.74; found 353.2 (M+H)⁻, t_(R)=11.97 min (Method 10).¹H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.08 (s, 1H), 8.00-7.75 (m,2H), 7.72 (d, J=6 Hz, 1H), 7.60-7.35 (m, 3H), 7.26 (bs, 1H), 7.04 (bs,1H), 5.38 (s, 2H).

Example 47 Synthesis of Compound 47-1

Step 47-1. Synthesis of1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one(INT 47-A)

Into a solution of INT 46-A (480 mg, 1.28 mmol) in Et₂O (20 mL) wasadded MeMgBr (0.557 mL of 3M solution in Et₂, 1.67 mmol). After thereaction mixture was stirred for 6 h, the reaction mixture was quenchedwith 0.1 m HCl (50 mL) and extracted into EA. The resulting organiclayer was washed with brine, dried (Na₂SO₄), filtered, concentrated, andpurified by SiO₂ chromatography (EA/hexanes) to provide 224 mg (53) of1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one(INT 47-A). LCMS-ESI (m/z) calculated for C₁₇H₁₅ClF₃NO₃: 373.07; m/z notobserved; t_(R)=6.2 min (Method 11).

Step 47-2. Synthesis of2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one (INT 47-B)

Into a solution of INT 47-A (224 mg, 0.68 mmol) in DCM (15 mL) was addedBr₂ (0.035 mL, 0.68 mmol). After the reaction mixture was stirred for 30min, the reaction mixture was quenched with NH₄Cl(aq) and extracted intoDCM. The resulting organic layer was washed with NaHCO₃ (sat, aq), waterand brine, dried (Na₂SO₄), concentrated, and purified by SiO₂chromatography (EA/hexanes) to provide 140 mg (50%) of2-bromo-1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)ethan-1-one(INT 47-B). LCMS-ESI (m/z) calculated for C₁₆H₁₁BrClF₃O₂: 405.96; found407.2 (M+H)*; t_(R)=5.529 min (Method 11).

Step 47-3. Synthesis of5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole(Compound 47-1)

A solution of INT 47-B (100 mg, 0.3 mmol) in formamide (5 mL) wasstirred for 4 h at 170° C., the reaction mixture was concentrated andpurified by reverse-phase C₁₈ chromatography (H₂O/MeOH) to provide 6 mg(5%) of5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-1H-imidazole(Compound 47-1). LCMS-ESI (m/z) calculated for C₁₇H₁₂ClF₃N₂O: 352.06;found 353.4 (M+H)*; t_(R)=12.14 min (Method 10).

Example 48 Synthesis of Compound 48-1

Step 48-1. Synthesis of (3-ethynylphenyl)methanol (INT 48-A)

Into a solution of (3-ethynylphenyl) methanol (1.5 g, 8.02 mmol) in TEA(8 mL) were added ethynyltrimethylsilane (1.58 g, 16 mmol), palladiumacetate (180 mg, 0.8 mmol), and PPh₃ (422 mg, 1.6 mmol). After stirringfor 1 h at 95° C., the reaction mixture was filtered through Celite andwashed with EA. The resulting organic layer was washed with H₂O (3×) andbrine, dried (Na₂SO₄), filtered, concentrated, and purified by SiO₂chromatography (EA/hexanes) to provide 800 mg (76%) of(3-ethynylphenyl)methanol (INT 48-A). LCMS-ESI (m/z) calculated forC₉H₈O. 132.06; found 133.3 (M+H)⁺, t_(R)=3.1 min (Method 11).

Step 48-2. Synthesis of2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B)

Into a solution of DEAD (55 mg of 40% solution, 2.7 mmol) in THE (3 mL)at 0° C. were added PPh₃ (71.2 mg, 2.7 mmol) and INT 48-A (30 mg, 8.02mmol). After the reaction mixture was stirred for 1 h, the reactionmixture was concentrated and purified by SiO₂ chromatography(EA/hexanes) to provide 65 mg (93%) of crude2-chloro-1-((3-ethynylbenzyl)oxy)-4-(trifluoromethyl)benzene (INT 48-B)that was carried onto the next step without further purification.

Step 48-3. Synthesis of4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole(Compound 48-1)

Into a solution of INT 48-B (65 mg, 2 mmol) in DMF (8 mL) and EtOH (1mL) was added CuI (122 mg, 0.64 mmol). The mixture was purged with N₂and TMSN₃ (741 mg, 6.4 mmol) was added. After stirring for 18 h at 120°C., the reaction mixture was filtered over Celite, concentrated, andpurified by SiO₂ chromatography (EA/hexanes) and reverse-phasechromatography (MeOH/H₂O with 0.1% TFA) to provide 65 mg (93%) of4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-2H-1,2,3-triazole(Compound 48-1). LCMS-ESI (m/z) calculated for C₁₆H₁₁ClF₃N₃O: 353.05;found 354.4 (M+H)⁺, t_(R)=5.39 min (Method 11).

Example 49 Synthesis of Compound 49-1

Step 49-1. Synthesis of5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-3-methyl-1,2,4-oxadiazole(Compound 49-1)

To a stirring solution of(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanol (500 mg, 2.6 mmol) inTHF (5 mL) were added triphenylphosphine (830 mg, 3.1 mmol) and DEAD(911 μL of a 70% solution, 3.2 mmol). After stirring for 2 h, thereaction mixture was diluted with EA and washed with sat. NaHCO₃, H₂O,and brine, then dried (Na₂SO₄), concentrated and purified by SiO₂chromatography (EA/hexane) to a residue that was triturated withMeOH/H₂O to afford 670 mg (69.1%) of5-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-3-methyl-1,2,4-oxadiazole(Compound 49-1). LCMS-ESI (m/z) calculated for C₁₇H₁₂ClF₃N₂O₂: 368.05;found 369.1 (M+H)⁺, t_(R)=14.59 min (50-95-4 min). ¹H NMR (300 MHz,DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.89 (bs, 1H), 7.80 (d,J=6.5 Hz, 1H), 7.50-7.30 (m, 2H), 7.46 (d, J=8.5 Hz, 1H), 5.46 (s, 2H),2.43 (s, 3H).

Example 50 Synthesis of Compound 50-1

Step 50-1. Synthesis of2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl) benzene(Compound 50-1)

To a stirring solution of (3-(difluoromethyl)phenyl)methanol (500 mg,2.26 mmol) in DMF (8 mL) were added 2-chloro-4-(trifluoromethyl)phenol(450 mg, 2.26 mmol) and Na₂CO₃ (720 mg, 6.79 mmol). After stirring for18 h at 50° C., the reaction mixture was diluted with H₂O, extractedinto EA, washed with H₂O and brine. The organic layers were concentratedSiO₂ chromatography (EA/hexane) to afford 165 mg (22%) of2-chloro-1-((3-(difluoromethyl)benzyl)oxy)-4-(trifluoromethyl)benzene(Compound 50-1). LCMS-ESI (m/z) calculated for C₁₅H₁₀ClF₅O. 336.03;found 359.2 (M+Na)+, t_(R)=5.68 min (Method 11). ¹H NMR (300 MHz, CDCl₃)7.70 (s, 1H), 7.63 (s, 1H), 7.625-7.45 (m, 4H), 7.04 (d, J=8.6 Hz, 1H),6.70 (t, J_(H-F)=56 Hz, 1H), 5.27 (s, 2H).

Example 52 Synthesis of Compound 52-1

Step 52-1. Synthesis ofN-benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl) benzamide(Compound 52-1)

To a stirring solution of Compound 1-55 (113 mg, 0.34 mmol) in DMF (5mL) were added HATU (137 mg, 0.36 mmol), DIPEA (126 mg, 0.98 mmol), andphenylmethanamine (35 mg, 0.33 mmol). After stirring for 16 h at rt, thereaction mixture was diluted with EA, washed with 30 mL each of H₂O, 1 MHC, 1 M NaOH, NaHCO₃ and brine. The organic layers were dried (Na₂SO₄),concentrated and purified by SiO₂ chromatography (EA/hexane) to afford62 mg (54%) ofN-benzyl-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzamide(Compound 52-1). LCMS-ESI (m/z) calculated for C₂₂H₁₇ClF₃NO₂: 5419.1;found 420.3 (M+H)⁺, t_(R)=12.98 min (Method 10). 1H NMR (400 MHz,DMSO-d6) δ 9.11 (s, 1H), 8.02 (s, 1H), 7.90-7.88 (m, 2H), 7.72 (d, J=8,1H), 7.65 (d, J=8, 1H), 7.54 (t, J=8, 1H), 7.45 (d, J=8, 1H), 7.33 (t,J=4, 4H), 7.26 (d, J=4, 1H), 55.38 (s, 2H), 4.49 (d, J=4, 1H).

The compounds listed in Table 52 were made using the procedures ofScheme 52.

TABLE 52 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

52-1 13.98 419.83 420.3 [M + H]⁺ 10

52-2 9.581 411.81 412.1 [M + H]⁺ 3

52-3 6.635 423.79 424 [M + H]⁺ 3

52-4 9.748 425.83 426.1 [M + H]⁺ 3

52-5 6.747 437.81 438.1 [M + H]⁺ 3

52-6 10.113 368.74 369.1 [M + H]⁺ 3

52-7 14.03 385.81 386.3 [M + H]⁺ 10

52-8 13.72 371.78 372 [M + H]⁺ 10

52-9 13.45 387.78 388.4 [M + H]⁺ 10

52-10 13.47 357.76 358.1 [M + H]⁺ 10

52-11 14.08 405.80 406.4 [M + H]⁺ 10

52-12 13.06 387.78 388.3 [M + H]⁺ 10

52-13 13.57 401.81 402.5 [M + H]⁺ 10

52-14 13.72 427.85 428.5 [M + H]⁺ 10

52-15 13.36 427.85 428.5 [M + H]⁺ 10

52-16 12.93 373.76 374.4 [M + H]⁺ 10

52-17 12.04 400.83 401.4 [M + H]⁺ 10

52-18 12.97 385.77 386.3 [M + H]⁺ 10

52-19 13.4 427.85 428.5 [M + H]⁺ 10

52-20 12.81 407.79 408.4 [M + H]⁺ 10

52-21 13.17 413.82 414.5 [M + H]⁺ 10

52-22 12.76 386.76 387.4 [M + H]⁺ 10

52-23 14.11 397.82 398.4 [M + H]⁺ 10

52-24 13.91 383.80 384.2 [M + H]⁺ 10

52-25 13.4 385.77 386.3 [M + H]⁺ 10

52-26 4.73 343.73 344.066 [M + H]⁺ 12

52-27 12.93 400.78 401.3 [M + H]⁺ 10

52-28 0.854 455.8 456 [M + H]⁺ 6

Example 53 Synthesis of Compound 53-1

Step 53-1. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzamide(Compound 53-1)

A solution of tert-butyl(2-(3-((2-chloro-4-(trifluoromethyl)phenoxy)m)methyl)benzamido) ethyl)(methyl)carbamate (50 mg, 0.099 mmol) (prepared from Compound 1-55 andtert-butyl (2-aminoethyl)(methyl)carbamate via Scheme 52) in 1:1 DCM:TFA (5 mL) was stirred for 16 h at rt. The reaction mixture wasconcentrated, dissolved in H₂O/CH₃CN and lyophilized to afford 30 mg(60%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-N-(2-(methylamino)ethyl)benzamide(Compound 53-1). LCMS-ESI (m/z) calculated for C₁₈H₁₈ClF₃N₂O₂: 386.1;found 387.4 (M+H)⁺, t_(R)=12.98 min (Method 10).

The compounds listed in Table 53 were made using the procedures ofScheme 53.

TABLE 53 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

53-1 13.64 386.80 387.4 [M + H]⁺ 10

53-2 11.85 372.77 373.3 [M + H]⁺ 10

Example 54 Synthesis of Compound 54-1

Step 54-1. Synthesis of(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine(Compound 54-1)

Into a solution of methyl(3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-valinate(250 mg, 0.56 mmol) (prepared from Compound 1-55 and methyl L-valinatevia Scheme 52) in EtOH (5 mL) was added 2M NaOH (1.12 g, 1.1 mmol).After stirring for 16 h at rt, the reaction mixture was diluted with EAand acidified with 1M HCl. The organic layer was collected and washedwith brine, dried (Na₂SO₄), concentrated, and purified withreverse-phase SiO₂ chromatography (MeOH/H₂O, with 0.1% formic acid) toafford 36 mg (15%) of(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-valine(Compound 54-1). LCMS-ESI (m/z) calculated for C₂₀H₁₉ClF₃NO₄: 429.1;found 430.6 (M+H)⁺, t_(R)=5.31 min (Method 11).

The compounds listed in Table 54 were made using the procedures ofScheme 54.

TABLE 54 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

54-1 13.63 429.82 430.3 [M + H]⁺ 10

54-2 13 387.74 388.3 [M + H]⁺ 10

54-3 13.27 415.79 416.5 [M + H]⁺ 10

54-4 13.15 401.77 402.6 [M + H]⁺ 10

54-5 13.62 516.90 517.2 [M + H]⁺ 10

54-6 13.18 401.77 402.6 [M + H]⁺ 10

54-7 12.95 493.86 494.4 [M + H]⁺ 10

54-8 12.89 431.79 432.2 [M + H]⁺ 10

54-9 12.71 417.77 418.5 [M + H]⁺ 10

54-10 13.82 449.81 450.2 [M + H]⁺ 10

54-11 13.61 449.81 450.2 [M + H]⁺ 10

54-12  0.972 405.73 406 [M + H]⁺  6

Example 55 Synthesis of Compound 55-1

Step 55-1. Synthesis of(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine(Compound 55-1)

A solution of tert-butyl(3-((2-chloro-4-(trifluoromethyl)phenoxy)-methyl)benzoyl)-L-asparaginate(200 mg, 0.4 mmol) (prepared from Compound 1-55 and tert-butylL-asparaginate via Scheme 52) in 1:1 TFA: DCM (5 mL) was stirred for 16h at rt. The mixture was concentrated and purified using reverse-phaseSiO₂ chromatography (MeOH/H₂, with 0.1% formic acid) to afford 107 mg(60%) of(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)benzoyl)-L-asparagine(Compound 55-1). LCMS-ESI (m/z) calculated for C₁₉H₁₆ClF₃N₂O₅: 444.1;found 445.4 (M+H)⁺, t_(R)=4.70 min (Method 11).

The compounds listed in Table 55 were made using the procedures ofScheme 55.

TABLE 55 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

55-1 12.54 444.79 445.4 [M + H]⁺ 10

55-2 10.92 467.83 468.4 [M + H]⁺ 10

55-3 12.58 458.82 459.4 [M + H]⁺ 10

Example 56 Synthesis of Compound 56-1

Step 56-1. Synthesis of ethyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate(Compound 56-1)

Into a solution of Compound 1-55 (30 mg, 0.086 mmol) in DCM (3 mL) wasadded thionyl chloride (19 μL, 0.26 mmol). After stirring for 2 h, thereaction mixture was concentrated and dissolved in EtOH (1 mL). After 1h, the mixture was concentrated and purified by RP-HPLC chromatographyto provide 32 mg (31%) of ethyl3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-fluorobenzoate(Compound 56-1). LCMS-ESI (m/z) calculated for C₁₇H₁₃ClF₄O₃: 376.7;found 378.1 (M+H)⁺, t_(R)=12.5 min (Escient purity).

The compounds listed in Table 56 were made using the procedures ofScheme 56.

TABLE 56 Purity Cpd RT observed Purity Structure No. (min) MW m/z IonMethod

56-1 12.50 376.73 378.1 [M + H]⁺ 3

56-2 11.30 359.73 360.1 [M + H]⁺ 3

Example 57 Synthesis of Compound 57-1

Step 57-1. Synthesis of dimethyl 4-methylpyridine-2,6-dicarboxylate (INT57-1)

Into a solution of 2,6-dichloro-4-methyl-pyridine (6.8 g, 41.97 mmol) inDMF (100 mL) and MeOH (50 mL) were added Pd(dppf)Cl₂—CH₂Cl₂ (3.43 g,4.20 mmol), TEA (23.37 mL. 167.9 mmol). The reaction was stirred at 80°C. under CO (1.18 g, 41.97 mmol, 50 Psi) for 16 h. The reaction mixturewas filtered, concentrated diluted with H₂O (100 mL) and extracted withEA (2×100 mL). The organic layer was collected, dried, filtered,concentrated, and purified by SiO₂ chromatography (EA/Petroleum ether)to provide 6.7 g (76%) of dimethyl 4-methylpyridine-2,6-dicarboxylate(INT 57-1) as a yellow solid. LCMS-ESI (m/z) calculated for C₁₀H₁₁NO₄:209.07; found 210.1 (M+H)⁺, t_(R)=0.742 min (Method 6).

Step 57-2. Synthesis of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT57-2)

Into a solution of INT 57-1 (6.7 g, 31.39 mmol) in MeOH (400 mL) and DCM(100 mL) at 0° C. was added NaBH₄ (1.78 g, 47.08 mmol) in smallportions. After stirring for 12 h at 0° C., the reaction mixture wasquenched by the addition of aqueous NH₄Cl (200 mL) and extracted into EA(3×200 mL). The combined organic layers were dried (Na₂SO₄), filtered,concentrated, and purified by SiO₂ chromatography to provide 3.7 g (64%)of methyl 6-(hydroxymethyl)-4-methylpicolinate (INT 57-2). LCMS-ESI(m/z) calculated for C₉H₁₁NO₃: 181.2; found 182.7 (M+H)⁺, t_(R)=0.323min (Method 6). ¹H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.35 (s, 1H),4.81 (s, 2H), 3.97 (s, 3H), 3.81-3.26 (m, 1H), 2.49-2.38 (s, 3H).

Step 57-3. Synthesis of methyl 6-(chloromethyl)-4-methylpicolinate (INT57-3)

Into a solution of INT 57-2 (200 mg, 1.1 mmol) in DCM (7 mL) at 0° C.was added SOCl₂ (1 mL, 13.8 mmol). After stirring for 1.5 h at rt, thereaction mixture was concentrated to provide 32 mg (31%) of methyl6-(chloromethyl)-4-methylpicolinate (INT 57-3) as a white solid that wasused without further purification. LCMS-ESI (m/z) calculated forC₉H₁₀ClNO₂: 199.04; found 200.0 (M+H)⁺, t_(R)=0.755 min (Method 6).

Step 57-4. Synthesis of6-(((2-chloro-4-(trifluoromethyl)phenyl)amino)methyl)-4-methylpicolinicacid (Compound 57-1)

Into a solution of INT 57-3 (200 mg, 1.0 mmol) and2-chloro-4-(trifluoromethyl) aniline (195.9 mg, 1.00 mmol) in DMF (3 mL)was added NaOH (400.7 mg, 10.02 mmol). The reaction mixture was stirredat 25° C. for 0.5 hr. The mixture was diluted with H₂O (10 mL), adjustedto pH=7 with HCl (36%), then filtered and concentrated to provide aresidue that was purified by reverse-phase prep HPLC (H₂O/CH₃CN with0.225% FA) to provide 2.2 mg (0.67%) of6-(((2-chloro-4-(trifluoromethyl)phenyl)amino)methyl)-4-methylpicolinicacid (Compound 57-1) as a white solid. LCMS-ESI (m/z) calculated forC₁₅H₁₂ClF₃N₂O₂: 344.05; found 345.0 (M+H)⁺, t_(R)=0.873 min (Method 6).¹H NMR (400 MHz, MeOD₄) 6 ppm 2.35-2.51 (s, 3H) 4.58-4.70 (s, 2H)6.60-6.81 (m, 1H) 7.26-7.35 ((m, 1H) 7.39-7.46 ((m, 1H) 7.50-7.60 (s,1H) 7.80-8.05 (s, 1H).

Example 58 Synthesis of Compounds 58-1 and 58-2

Step 58-1. Synthesis of methyl1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (INT 58-1)

Step 58-1

Pd(dppf)Cl₂.DCM (285 mg, 0.35 mmol) was added to a solution of5-bromo-3,4-dihydro-2H-isoquinolin-1-one (395 mg, 1.75 mmol) and TEA(1.22 mL, 8.74 mmol) in DMF (6.00 mL) at 22° C. The mixture wasevacuated and refilled with CO for 3 cycles. MeOH (3.08 mL) was added,and the mixture was heated to 85° C. under a CO atmosphere (1 atm) for16 h. The mixture was diluted with EA (25 mL) and filtered through a padof Celite. The filtrate was concentrated under reduced pressure. Theresidue was diluted with EA (100 mL) and H₂O (100 mL). The aq. phase wasextracted with EA (3×25.0 mL). The combined organic layers were washedwith brine (50 mL), dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by SiO₂ chromatography (hexanes and EA) to provide285 mg (80%) of methyl1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (INT 58-1). LCMS-ESI(m/z) calculated for C₁₁H₁₁NO₃: 205.07; found 205.74 (M+H)⁺, t_(R)=1.82min (Method 13). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=7.7, 1.5 Hz, 1H),8.09 (dd, J=7.8, 1.5 Hz, 1H), 7.42 (dd, J=7.8 Hz, 1H), 5.95 (s, 1H),3.92 (s, 3H), 3.58-3.52 (m, 2H), 3.49-3.40 (m, 2H).

Step 58-2. Synthesis of5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2)

LiBH₄ (2 M in THF, 2.66 mL, 5.32 mmol) was added to a solution of INT58-1 (182 mg, 0.887 mmol) in THE (5.00 mL) at 22° C. under N₂. Themixture was stirred at 22° C. for 20 h. The mixture was diluted withsat. aq. NH₄Cl (10 mL). The aq. phase was extracted with EA (3×20 mL),and the combined organic phases were washed with brine (50 mL), dried(Na₂SO₄), filtered, and concentrated to provide 88 mg (56%) of5-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (INT 58-2) as an oil.LCMS-ESI (m/z) calculated for C₁₀H₁NO₂: 177.08; found 178.13 (M+H)⁺,t_(R)=1.39 min (Method 13). ¹H NMR (500 MHz, CDCl₃) δ 8.07 (dd, J=7.8,1.4 Hz, 1H), 7.52 (dd, J=7.6, 1.4 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 5.95(s, 1H), 4.75 (s, 2H), 3.57 (td, J=6.7, 2.9 Hz, 2H), 3.07 (t, J=6.6 Hz,2H), 1.72 (s, 1H).

Step 58-3. Synthesis of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 58-1)

DIAD (108 μL, 0.55 mmol) was added to a mixture of INT 58-2 (88.0 mg,0.497 mmol), 2-chloro-4-(trifluoromethyl)phenol (69.7 μL, 0.521 mmol),and PPh₃ (143 mg, 0.546 mmol) in THE (5.00 mL) at 0° C. under N₂. Themixture was stirred at 22° C. for 18 h. The mixture was concentrated,and the residue was purified by reverse phase chromatography (H₂O (+0.1%formic acid) and MeCN) to provide 32.7 mg (19%) of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 58-1) as a solid. LCMS-ESI (m/z) calculated for C₁₇H₁₃ClF₃NO₂:355.06; found 356.07 (M+H)⁺, t_(R)=4.69 min (Method 12). ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, 1H), 7.90 (dd, J=7.8, 1.4 Hz, 1H), 7.88-7.85 (m,1H), 7.73 (ddd, J=8.7, 2.3, 0.9 Hz, 1H), 7.68 (dd, J=7.6, 1.4 Hz, 1H),7.52 (d, J=8.6 Hz, 1H), 7.40 (dd, J=7.6 Hz, 1H), 5.38 (s, 2H), 3.38 (td,J=6.6, 2.8 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H).

Step 58-4. Synthesis of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one(Compound 58-2)

NaH (24.9 mg, 1.08 mmol) was added to a solution of Compound 58-1 (154mg, 50% purity, 0.216 mmol) in THE (5.00 mL) at 0° C. under N₂. Themixture was stirred at 22° C. for 30 min. Iodomethane (67.4 μL, 1.08mmol) was added, and the mixture was stirred at 70° C. for 1 h. Themixture was diluted with MeOH (10.0 mL) and concentrated. The productwas purified by reverse phase chromatography (H₂O (+0.1% formic acid)and MeCN) to provide 60 mg (76%) of5-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one(Compound 58-2) as an solid. LCMS-ESI (m/z) calculated forC₁₈H₁₅ClF₃NO₂: 369.77; found 370.08 (M+H)⁺, t_(R)=5.08 min (Method 12).¹H NMR (500 MHz, CDCl₃) δ 8.00 (s, 1H), 7.92 (dd, J=7.8, 1.4 Hz, 1H),7.86 (dd, J=2.3, 0.7 Hz, 1H), 7.73 (ddd, J=8.7, 2.3, 0.8 Hz, 1H), 7.66(dd, J=7.6, 1.4 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.39 (dd, J=7.7 Hz,1H), 5.38 (s, 2H), 3.56 (t, J=6.7 Hz, 2H), 3.07-2.99 (m, 4H).

Example 59 Synthesis of Compound 59-1

Step 59-1. Synthesis of (3-vinylphenyl)methanol (INT 59-1)

NaBH₄ (327 mg, 8.66 mmol) was slowly added to a solution of3-vinylbenzaldehyde (1.00 mL, 7.87 mmol) in MeOH (20 mL) at 22° C. underN₂. The mixture was stirred at 22° C. for 1 h and concentrated underreduced pressure. The residue was purified by SiO₂ chromatography(EA/hexanes) to provide 1.05 g (99%) of (3-vinylphenyl) methanol (INT59-1). LCMS-ESI (m/z) mass not observed, t_(R)=2.00 min (Method 13). ¹HNMR (400 MHz, CDCl₃) δ 7.42 (s, 1H), 7.37-7.30 (m, 2H), 7.26 (d, J=3.1Hz, 1H), 6.73 (dd, J=17.6, 10.9 Hz, 1H), 5.78 (dd, J=17.6, 0.9 Hz, 1H),5.27 (dd, J=10.9, 0.9 Hz, 1H), 4.70 (s, 2H), 1.67 (s, 1H).

Step 59-2. Synthesis of2-chloro-4-(trifluoromethyl)-1-((3-vinylbenzyl)oxy)benzene (INT 59-2)

DIAD (1.29 mL, 6.56 mmol) was added dropwise to a mixture of INT 59-1(800 mg, 5.96 mmol), 2-chloro-4-(trifluoromethyl)phenol (793 mL, 5.93mmol), and PPh₃ (2.35 g, 8.94 mmol) in THE (15.0 mL) at 22° C. under N₂.The mixture was stirred at 22° C. for 6 h and concentrated. The residuewas purified by SiO₂ chromatography (EA/hexanes) to provide 1.73 g (93%)of 2-chloro-4-(trifluoromethyl)-1-((3-vinylbenzyl)oxy)benzene (INT 59-2)as an oil. LCMS-ESI (m/z) mass not observed, t_(R)=2.95 min (Method 13).¹H NMR (500 MHz, CDCl₃) δ 7.66 (dd, J=2.3, 0.7 Hz, 1H), 7.49 (s, 1H),7.48-7.43 (m, 1H), 7.41-7.35 (m, 3H), 7.06-6.99 (m, 1H), 6.74 (dd,J=17.6, 10.9 Hz, 1H), 5.78 (dd, J=17.6, 0.9 Hz, 1H), 5.29 (dd, J=10.9,0.8 Hz, 1H), 5.21 (s, 2H).

Step 59-3. Synthesis of4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)azetidin-2-one(Compound 59-1)

N-Chlorosulfonyl isocyanate (578 μL, 6.64 mmol) was added over 10 min toa solution of INT 59-2 (1.73 g, 5.53 mmol) in THE (5.00 mL) at 22° C.under N₂. The mixture was stirred at 22° C. for 16 h. The mixture wasadded over 20 min to a vigorously stirred mixture of H₂O (10.0 mL),sodium carbonate (1.93 g, 18.3 mmol), and sodium sulfite (1.05 g, 8.30mmol) at 0° C. The mixture was stirred at 22° C. for 2 h. The mixturewas acidified with aq. 1 M HCl (pH 5) and diluted with EA (100 mL). Theaq. phase was extracted with EA (3×50.0 mL), and the combined organiclayers were dried (MgSO₄), filtered, and concentrated. The residue waspurified by reverse phase chromatography (H₂O (+0.1% formic acid) andMeCN (50-100%) to provide 189 mg (10%) of4-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)azetidin-2-one(Compound 59-1) as an solid. LCMS-ESI (m/z) calculated forC₁₇H₁₃ClF₃NO₂: 355.06; found 356.07 (M+H)⁺, t_(R)=4.93 min (Method 12).¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H), 7.86 (dd, J=2.3, 0.7 Hz, 1H),7.75-7.67 (m, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.48-7.38 (m, 3H), 7.36 (dt,J=6.8, 2.1 Hz, 1H), 5.33 (s, 2H), 4.67 (dd, J=5.3, 2.5 Hz, 1H), 3.36(ddd, J=14.6, 5.3, 2.2 Hz, 1H), 2.67 (ddd, J=14.6, 2.5, 1.0 Hz, 1H).

Example 60 Synthesis of Compound 60-1

Step 60-1. Synthesis of methyl 3-bromo-5-iodo-benzoate (INT 60-1)

H₂SO₄ (600 μL, 11.3 mmol) was added to a solution of3-bromo-5-iodo-benzoic acid (10.0 g, 30.6 mmol) in MeOH (65 mL). Themixture was stirred at 75° C. for 18 h. The mixture was cooled to 22° C.and concentrated. The residue was diluted in EA (100 mL), washed withsat. aq. NaHCO₃ (100 mL), dried (Na₂SO₄), filtered, and concentrated toprovide 9.90 g (95%) of methyl 3-bromo-5-iodo-benzoate (INT 60-1) as asolid. LCMS-ESI (m/z) calculated for C₈H₆BrIO₂: 339.86; found 339.6(M−H)+, t_(R)=2.72 min (Method 13).

Step 60-2. Synthesis of methyl 3-bromo-5-cyanobenzoate (INT 60-2)

Zinc cyanide (1.76 g, 15.0 mmol) and Pd(PPh₃)₄ (2.88 g, 2.49 mmol) wereadded to a solution of INT 60-1 (8.50 g, 2.49 mmol) in DMF (60 mL). Themixture was stirred at 80° C. for 2 h. The mixture was cooled to 22° C.and concentrated. The residue was diluted with EA (100 mL). The organiclayer was washed with H₂O (3×50.0 mL) and brine (150 mL), dried(Na₂SO₄), filtered, and concentrated. The residue was purified by SiO₂chromatography (EA/hexanes) to provide 3.00 g (50%) of methyl3-bromo-5-cyanobenzoate (INT 60-2) as a solid. LCMS-ESI (m/z): mass notobserved, t_(R)=2.38 min (Method 13).

Step 60-3. Synthesis of methyl3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT60-3)

2-Chloro-1-ethynyl-4-(trifluoromethyl)benzene (551 μL, 1.87 mmol),PdCl₂(PPh₃)₂ (132 mg, 0.19 mmol), and CuI (17.9 mg, 0.094 mmol) wereadded to a solution of INT 60-2 (225 mg, 0.94 mmol) in 1,4-dioxane (2mL) and Et₃N (2.0 mL). The mixture was stirred at 80° C. for 24 h. Themixture was cooled to 22° C. and diluted with aq. sat. NH₄Cl (20 mL).The aq. phase was extracted with EA (3×50 mL), and the combined organiclayers were concentrated. The residue was purified by SiO₂chromatography (EA/hexanes) to provide 250 mg (73%) of methyl3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoate (INT60-3) as a solid. LCMS-ESI (m/z) calculated for C₁₈H₉ClF₃NO₂: 363.03;found 365.5 (M+H)⁺, t_(R)=2.92 min (Method 13). ¹H NMR (400 MHz, CDCl₃)δ 8.42 (t, J=1.5 Hz, 1H), 8.30 (t, J=1.4 Hz, 1H), 8.00 (t, J=1.4 Hz,1H), 7.72 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 3.99(s, 3H).

Step 60-4. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid(Compound 60-1)

Aq. 2 M NaOH (165 μL, 0.330 mmol) was added to a solution of INT 60-3(60.0 mg, 0.165 mmol) in THE (2 mL) at 22° C. The mixture was stirred at22° C. for 12 h and concentrated. The residue was diluted with H₂O (10.0mL) and acidified with aq. 2 M HCl (pH 2). The aq. phase was extractedwith EA (3×20.0 mL), and the combined organic layers were dried(Na₂SO₄), filtered, and concentrated. The residue was purified by SiO₂chromatography (MeOH/DCM) to provide 55.0 mg (95%) of3-((2-chloro-4-(trifluoromethyl)phenyl)ethynyl)-5-cyanobenzoic acid(Compound 60-1) as a solid. LCMS-ESI (m/z) calculated for C₁₇H₇ClF₃NO₂:349.01; found 348.49 (M−H)+, t_(R)=4.55 min (Method 12). ¹H NMR (400MHz, DMSO-d6) δ 8.37-8.32 (m, 2H), 8.30 (s, 1H), 8.08 (s, 1H), 7.97 (d,J=8.0 Hz, 1H), 7.82 (dd, J=8.1, 1.1 Hz, 1H).

Example 61 Synthesis of Compound 61-1

Step 61-1. Synthesis of methyl3-(2-(2-chloro-4-(trifluoromethyl)phenyl)ethyl)-5-cyano-benzoate (INT61-1)

INT 60-3 (100 mg, 0.275 mmol) and Pd/C (100 mg, 0.0940 mmol) in EA (10.0mL) were stirred under hydrogen (1 atm) at 22° C. for 4 h. The mixturewas filtered through Celite, washing with EA (100 mL), and the filtratewas concentrated. The residue was purified by SiO₂ chromatography(EA/hexanes) to provide 101 mg (100%) methyl3-[2-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]-5-cyano-benzoate (INT61-1) as a solid. LCMS-ESI (m/z) calculated for C₁₈H₁₃ClF₃NO₂: 367.06;found 367.3 (M−H)+, t_(R)=2.85 min (Method 13).

Step 61-2. Synthesis of3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid (Compound61-2)

A solution of 2 M NaOH (197 μL, 0.156 mmol) was added to a solution ofINT 61-1 (60.0 mg, 0.156 mmol) in THE (2 mL). The mixture was stirred at22° C. for 12 h and concentrated. The residue was acidified with 2 M HCl(pH 2) and diluted with H₂O (10 mL). The aq. phase was extracted with EA(3×20 mL), and the combined organic layers were dried (Na₂SO₄),filtered, and concentrated. The residue was purified by reverse phasechromatography (H₂O (+0.1% formic acid) and ACN) to provide 47.0 mg(85%) of 3-(2-chloro-4-(trifluoromethyl)phenethyl)-5-cyanobenzoic acid(Compound 61-2) as a solid. LCMS-ESI (m/z) calculated for C₁₇H₁₁ClF₃NO₂:353.04; found 352.1 (M−H)+, t_(R)=4.73 min (Method 12). ¹H NMR (500 MHz,DMSO-d6) δ 13.54 (s, 1H), 8.13 (t, J=1.5 Hz, 1H), 8.05 (t, J=1.6 Hz,1H), 7.98 (t, J=1.6 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.66 (dd, J=8.0,1.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 3.07 (dq, J=9.8, 6.3 Hz, 4H).

Example 62 Synthesis of Compound 62-1

Step 62-1. Synthesis of methyl 3-(1-hydroxyethyl)benzoate (INT 62-1)

NaBH₄ (752 mg, 19.9 mmol) was added to a mixture of methyl3-acetylbenzoate (1.18 g, 6.62 mmol) in EtOH (15.0 mL) at 22° C. Themixture was stirred at 0° C. for 30 min and at 22° C. for 1 h. Themixture was diluted with sat. aq. NH₄Cl (30.0 mL). The aq. phase wasextracted with EA (3×30.0 mL), and the combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby SiO₂ chromatography (EA/hexanes) to provide the 830 mg (70%) ofmethyl 3-(1-hydroxyethyl) benzoate (INT 62-1) as a solid. LCMS-ESI (m/z)mass not observed, t_(R)=1.93 min (Method 12). ¹H NMR (400 MHz, CDCl₃) δ8.05 (tt, J=1.8, 0.6 Hz, 1H), 7.98-7.92 (m, 1H), 7.59 (dddd, J=7.7, 1.8,1.2, 0.6 Hz, 1H), 7.43 (tt, J=7.7, 0.4 Hz, 1H), 4.97 (q, J=6.5 Hz, 1H),3.92 (s, 3H), 1.84 (s, 1H), 1.52 (d, J=6.5 Hz, 3H).

Step 62-2. Synthesis of methyl3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT 62-2)

DIAD (981 μL, 4.98 mmol) was added to a mixture of INT 62-1 (816 mg,4.53 mmol), 2-chloro-4-(trifluoromethyl)phenol (886 mg, 4.51 mmol), andPPh₃ (1.78 g, 6.79 mmol) in THE (25.0 mL) at 22° C. The mixture wasstirred at 22° C. for 3 h. The mixture was concentrated, and the residuewas purified by SiO₂ chromatography (EA/hexane) to provide 1.40 g (86%)of methyl 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoate (INT62-2) as a solid. LCMS-ESI (m/z) calculated for C₁₇H₁₄ClF₃O₃: 358.06;found 357.06 (M−H)+, t_(R)=2.87 min (Method 13).

Step 62-3. Synthesis of3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (Compound62-1)

2 M NaOH (4.68 mmol, 2.34 mL) was added to a solution of INT 62-2 (1.40g, 3.90 mmol) in MeOH (12 mL) and THE (12 mL) at 22° C. After 12 h, themixture was concentrated, and the residue was diluted with H₂O (10.0 mL)and 2 M HCl (pH 4). The aq. phase was extracted with EA (3×25.0 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated,and the residue was purified by SiO₂ chromatography (MeOH/DCM) toprovide 1.34 g (99%) of3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)benzoic acid (Compound62-1) as a solid. LCMS-ESI (m/z) calculated for C₁₆H₁₂ClF₃O₃: 344.04;found 343.04 (M−H), t_(R)=5.17 min (Method 12). ¹H NMR (400 MHz,DMSO-d6) δ 13.04 (s, 1H), 8.03 (t, J=1.6 Hz, 1H), 7.90-7.84 (m, 1H),7.82 (d, J=2.0 Hz, 1H), 7.71-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50 (t,J=7.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 5.89 (q, J=6.3 Hz, 1H), 1.62 (d,J=6.3 Hz, 3H).

Example 63 Synthesis of Compound 63-1

Step 63-1. Synthesis of tert-butylN-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate (INT 63-1)

tert-Butyl N-((3-(bromomethyl)phenyl)methyl)carbamate (100 mg, 0.333mmol) was added to a mixture of 2-chloro-4-(trifluoromethyl)phenol (50.0μL, 0.366 mmol) and K₂CO₃ (51.0 mg, 0.366 mmol) in DMF (1 mL) at 22° C.under N₂. The mixture was stirred at 40° C. for 16 h. The mixture wasdiluted with H₂O (20 mL), and the aq. layer was extracted with DCM (3×20mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated. The residue was purified by SiO₂ chromatography(EA/hexanes) to provide 122 mg (88%) of tert-butylN-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)carbamate(INT 63-1). LCMS-ESI (m/z) calculated for C₂₀H₂₁ClF₃NO₃: 415.12; found414.17 (M+H)⁺, t_(R)=2.86 min (Method 13). ¹H NMR (400 MHz, CDCl₃) δ7.66 (d, J=2.3 Hz, 1H), 7.45 (ddd, J=8.6, 2.2, 0.9 Hz, 1H), 7.40-7.33(m, 3H), 7.28-7.27 (m, 1H), 7.01 (d, J=8.6 Hz, 1H), 5.20 (s, 2H), 4.86(s, 1H), 4.34 (d, J=6.0 Hz, 2H), 1.46 (s, 9H).

Step 63-2. Synthesis of tert-butylN-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-carbamate (INT 63-2)

NaH (60 wt. % 12.2 mg, 0.317 mmol) was added to a solution of INT 63-1(120 mg, 0.289 mmol) in THE (2 mL) at 22° C. under N₂. The mixture wasstirred at 22° C. for 15 min. Iodomethane (21.6 μL, 0.346 mmol) wasadded, and the mixture was stirred at 50° C. for 24 h. The mixture wasconcentrated, and the residue was purified by SiO₂ chromatography(EA/hexanes) to provide 71.2 mg (57%) of tert-butylN-((3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)methyl)-N-methyl-carbamate(INT 63-2). LCMS-ESI (m/z) calculated for C₂₁H₂₃ClF₃NO₃: 429.13; found428.17 (M−H)+, t_(R)=3.29 min (Method 13). ¹H NMR (500 MHz, CDCl₃) δ7.66 (d, J=2.2 Hz, 1H), 7.48-7.43 (m, 1H), 7.38-7.33 (m, 2H), 7.30 (s,1H), 7.21 (s, 1H), 7.01 (d, J=8.6 Hz, 1H), 5.20 (s, 2H), 4.45 (s, 2H),2.82 (d, J=26.0 Hz, 3H), 1.47 (d, J=15.5 Hz, 9H).

Step 63-3. Synthesis of1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine(Compound 63-1)

A solution of TFA (500 μL) was added dropwise to a solution of INT 63-2(70.0 mg, 0.745 mmol) in DCM (1.5 mL). The mixture was stirred at 22° C.for 5 h. The mixture was basified with aq. 1 M NaOH (10 mL) and stirredat 22° C. for 15 min. The aq. phase was extracted with DCM (3×20 mL),and the combined organic layers were washed with brine (20 mL), dried(MgSO₄), filtered, and concentrated. The residue was purified by reversephase chromatography (H₂O (+0.03% ammonium carbonate)/MeCN) to providethe free form as an oil. HCl (2 M in Et₂O, 121 μL, 0.121 mmol) was addedto a solution of the free form (40.0 mg, 0.121 mmol) in Et₂O (2 mL) at22° C. After 10 min, the mixture was concentrated to provide 42.2 mg(70%) of1-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)phenyl)-N-methylmethanamine(Compound 63-1). LCMS-ESI (m/z) calculated for C₁₆H₁₅ClF₃NO. 329.08;found 330.09 (M+H)⁺, t_(R)=3.87 min (Method 12). ¹H NMR (500 MHz, CDCl₃)δ 8.98 (s, 2H), 7.88 (d, J=2.5 Hz, 1H), 7.71 (dd, J=8.7, 2.3 Hz, 1H),7.59 (d, J=1.5 Hz, 1H), 7.54 (qd, J=4.0, 3.5, 1.6 Hz, 1H), 7.53-7.50 (m,2H), 7.45 (d, J=8.7 Hz, 1H), 5.34 (s, 2H), 4.15 (s, 2H), 2.56 (s, 3H).

Example 64 Synthesis of Compound 64-1

Step 64-1. Synthesis of 2-(3-(hydroxymethyl)phenyl)acetonitrile (INT64-1)

To a solution of methyl 3-(cyanomethyl)benzoate (3 g, 17.1 mmol) in THF(150 ml) was added NaBH₄ (1.3 g, 34 mmol) in 5 portions. The mixture washeated to 80° C. and stirred for 30 min. After cooling to rt, MeOH wasadded dropwise and the mixture was stirred at 80° C. for 30 min and atrt for 16 h. The solution was quenched with H₂O (30 mL) andconcentrated. The resulting residue was diluted with H₂O and extractedwith EA. The organic layer was washed with H₂O then brine, dried(Na₂SO₄), filtered and concentrated. The resulting crude residue waspurified by SiO₂ chromatography (EA/hexane) to provide 1.0 g (40%) of2-(3-(hydroxymethyl)phenyl)acetonitrile (INT 64-1). LCMS-ESI (m/z)calculated for C₉H₉NO: 147.07; found 170.3 (M+H₂O)*, t_(R)=2 min (Method11).

Step 64-2. Synthesis of2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2)

To a solution of DIAD (495 mg, 2.4 mmol) in THE (10 mL) was added PPh₃(641 mg, 2.4 mmol) and stirred for 10 min. A solution of INT 64-1 (300mg, 0.2 mmol) in THF (5 mL) was then added followed by a solution of2,4-dichlorophenol (332 mg, 2 mmol) in THE (5 mL). The reaction wasstirred at rt for 16 h, diluted with EA and washed consecutive withsaturated NaHCO₃(aq), and brine, then dried over (Na₂SO₄), filtered andconcentrated. The resulting crude residue was purified twice by SiO₂chromatography (EA/hex) to provide 0.21 g (35%) of2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetonitrile (INT 64-2). ¹H NMR(400 MHz, CDCl₃) δ 7.27-7.5 (m, 5H), 7.16 (d, J=8 Hz, 1H), 6.87 (d, J=8Hz, 1H), 5.13 (s, 2H), 3.77 (s, 2H).

Step 64-3. Synthesis of 2-(3-((2,4-dichlorophenoxy)methyl)phenyl)aceticacid (Compound 64-1)

INT 64-2 (100 mg, 0.34 mmol) was dissolved in a solution of NaOH (aq,2M, 5 mL) and heated to 130° C. in a sealed tube for 24 h. The reactionmixture was acidified with 1M HCl and extracted with EA. The organiclayer was dried washed with brine, dried (Na₂SO₄), filtered andconcentrated. The resulting residue was dried further under high vacuumto provide 20 mg (19%) of2-(3-((2,4-dichlorophenoxy)methyl)phenyl)acetic acid (Compound 64-1).LCMS-ESI (m/z) mass not observed, t_(R)=13.8 min (Method 10). ¹H NMR(400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.40-7.30 (m, 4H), 7.30-7.20 (m, 2H),5.20 (s, 2H), 3.59 (s, 2H).

Example 65 Synthesis of Compound 65-1

Step 65-1. Synthesis of2-chloro-1-((3-nitrobenzyl)oxy)-4-(trifluoromethyl)benzene (INT 65-1)

Into a 250 mL flask were added 1-(bromomethyl)-3-nitrobenzene (1.0 g,4.37 mmol), 2-chloro-4-(trifluoromethyl)phenol (858 mg, 4.37 mmol),Na₂CO₃ (1.39 g, 13 mmol) and DMF (50 mL). After stirring at 50° C. for18 h, the reaction was quenched with H₂O and extracted into EA. Theorganic layers were dried (Na₂SO₄), concentrated and purified by SiO₂chromatography (EA/Hexane) to provide 1.0 g (69%) of2-chloro-1-((3-nitrobenzyl) oxy)-4-(trifluoromethyl) benzene (INT 65-1).LCMS-ESI no mass observed, t_(R)=5.66 min (Method 11).

Step 65-2. Synthesis of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (Compound 65-1)

INT 65-1 (1.0 g, 3.02 mmol) was dissolved in MeOH (10 mL) and excess 2NHCl and Fe powder (210 mg, 3.77 mmol) were added. The reaction mixturewas heated to 80° C. for 18 h, filtered through Celite, concentrated,and purified over SiO₂, (EA/hexane). The resulting material was furtherpurified by reverse-phase chromatography (MeOH/H₂O with 0.1% formicacid) to provide 800 mg (60%) of3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)aniline (Compound 65-1).LCMS-ESI (m/z) calculated for C₁₄H₁₁ClF₃NO. 301.05; found 302.1 (M+H)⁺,t_(R)=2 min (Method 11).

Example 66 MRGPRX4 Activity

HEK cells stably transfected to express human MRGPR X4 were maintainedin an incubator at 37° C. with 5% CO₂ and grown in DMEM media with 10%fetal bovine serum (FBS) and 1% each of sodium pyruvate, Glutamax,penicillin/streptomycin, and Geneticin. HEK cells stably transfected toexpress mouse MRGPR A1 were maintained in the same incubator and grownin DMEM media with 10% FBS, 1% each of sodium pyruvate, Glutamax,penicillin/streptomycin, Geneticin, and 2.2 mg/mL Hygromycin.

Cells were plated in a 384-well assay plate at 20,000 cells per well in12 μL of Opti-MEM and kept in an incubator overnight. On the day of theassay, compounds solubilized at 10 mM in DMSO were added as a 10-pointcurve (10 uM final top concentration with 1:3 serial dilutions) using aTecan D300E digital dispenser. Agonists were diluted in assay buffer(final concentrations of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH=8)and 2 μL of the appropriate agonist are added to each well. Finalconcentrations of agonists were 10 μM bilirubin, 20 μM deoxycholic acid,or 100 μM conjugated bilirubin (obtained from Lee Biosolutions, catalog#910-12). Final concentrations of DMSO were kept consistent across theplate. Plates were incubated in the dark for 1 h at 37° C. and then for30 minutes at room temperature. IP-1 standards and HTRF detectionreagents were added according to the IP-One-Gq Kit purchased from Cisbio(part number 62IPAPEJ) and incubated in the dark for 1 h at roomtemperature. The plate was read on a Molecular Devices SpectraMax iD5plate reader. The HTRF ratio was calculated from the raw data andgraphed using GraphPad Prism to calculate an IC₅₀ value for eachcompound.

Activity data for selected MRGPR X4 antagonists (versus 10 μM Bilirubinagonist) are displayed in Table 66A. The activity ranges are denoted asfollows: “+++++” denotes antagonist activity <100 nM; “++++” denotesantagonist activity between 100 and 500 nM; “+++” denotes activitybetween 500 and 1000 nM; “++” denotes activity between 1000 and 2500 nM;and “+” denotes activity >2500 nM.

TABLE 66A MRGPR4 Antagonist Cpd No. Activity 1-1 ++ 1-2 ++++ 1-3 ++1-4 + 1-5 ++++ 1-6 ++ 1-7 ++ 1-8 + 1-9 ++ 1-10 +++ 1-11 +++++ 1-12 +++++1-13 ++++ 1-14 ++ 1-15 ++ 1-16 +++++ 1-17 ++++ 1-18 +++++ 1-19 ++ 1-20++ 1-21 ++++ 1-22 + 1-23 +++ 1-24 + 1-25 + 1-26 ++ 1-27 + 1-28 ++++ 1-29+++++ 1-30 +++++ 1-31 +++++ 1-32 ++ 1-33 ++ 1-34 + 1-35 ++++ 1-36 +++1-37 ++++ 1-38 ++++ 1-39 ++++ 1-40 ++ 1-41 ++++ 1-42 ++ 1-43 +++ 1-44+++ 1-45 ++ 1-46 ++ 1-47 ++++ 1-48 + 1-49 +++ 1-50 ++ 1-51 ++ 1-52 +1-53 +++ 1-54 + 1-55 +++++ 1-56 +++++ 1-57 ++++ 1-58 +++++ 1-59 +++++1-60 +++ 1-61 +++ 1-62 +++++ 1-63 +++++ 1-64 +++++ 1-65 +++++ 1-66 +++1-67 +++ 1-68 ++++ 1-69 +++ 1-70 ++ 1-71 +++ 1-72 +++ 1-73 +++++ 1-74 +1-75 ++ 1-76 ++++ 1-77 ++ 1-78 +++++ 1-79 ++++ 1-80 ++++ 1-81 + 1-82+++++ 1-83 ++++ 1-84 ++ 1-85 +++++ 1-86 +++ 1-87 ++ 1-88 ++ 1-89 ++++1-90 ++++ 1-91 +++ 1-92 ++ 1-94 ++ 1-95 ++++ 1-96 +++ 1-97 ++++ 1-98 +++1-99 ++++ 1-100 + 1-101 +++++ 1-102 ++ 1-103 +++++ 1-108 ++ 1-109 +++1-110 ++++ 1-112 +++++ 1-113 +++ 1-114 ++ 1-115 +++++ 1-116 +++ 1-117+++ 1-118 +++++ 1-119 +++++ 1-120 +++++ 1-121 ++++ 1-122 ++++ 1-123+++++ 1-124 +++++ 1-125 +++++ 1-126 ++ 1-127 +++++ 1-128 +++ 1-129 +++++1-130 ++++ 1-131 ++++ 1-132 +++++ 1-133 +++++ 1-134 ++++ 1-135 ++++1-136 +++++ 1-137 ++++ 1-138 + 1-139 + 1-140 ++ 1-141 ++ 1-142 ++++1-143 +++++ 1-144 + 1-145 ++++ 1-146 + 1-147 ++ 1-148 +++++ 1-149 +++++1-150 + 1-151 + 1-152 ++ 1-153 ++++ 1-154 ++++ 2-1 +++++ 2-2 +++++ 2-3+++++ 2-4 +++++ 3-1 +++ 3-2 +++ 3-3 ++ 3-4 ++++ 3-5 ++++ 3-6 ++++ 3-7 ++3-8 ++ 3-9 ++ 4-1 +++++ 4-2 ++ 4-3 ++++ 4-4 +++++ 4-5 +++++ 4-6 ++++ 4-7+++++ 4-8 ++++ 4-9 +++++ 4-10 +++++ 4-11 +++++ 4-12 +++++ 4-13 +++++4-14 +++++ 4-15 +++++ 4-16 ++++ 4-17 +++++ 4-18 +++++ 4-19 +++++ 4-20++++ 4-21 +++++ 4-22 ++++ 4-23 +++ 4-24 +++ 4-25 ++++ 4-26 +++++ 4-27++++ 4-28 +++++ 4-29 + 5-1 +++++ 5-2 ++ 6-1 ++ 7-1 ++++ 8-1 + 8-2 ++ 8-3+++++ 8-4 +++ 9-1 +++++ 9-2 +++++ 9-3 +++++ 10-1 ++ 11-1 +++++ 12-1 ++++12-2 +++ 12-3 +++++ 12-4 +++++ 13-1 + 14-1 ++ 15-1 ++++ 16-1 ++ 16-2 +17-1 ++++ 17-2 +++++ 17-3 ++++ 17-4 +++++ 17-5 +++++ 17-6 +++++ 17-7+++++ 17-8 +++++ 17-9 +++++ 17-10 +++++ 17-11 +++++ 17-12 +++ 17-13+++++ 17-14 +++++ 17-15 +++++ 17-16 +++++ 32-1 +++++ 32-2 +++++ 32-3+++++ 32-4 +++++ 32-5 +++++ 33-1 + 33-2 ++++ 33-3 +++++ 33-4 ++++ 34-1+++ 35-1 ++++ 36-1 +++ 37-1 ++ 38-1 ++++ 39-1 +++++ 40-1 +++ 41-1 +++++41-2 +++++ 42-1 +++++ 42-2 +++++ 42-3 +++++ 43-1 +++++ 44-1 ++++ 45-1++++ 45-2 +++ 46-1 ++++ 47-1 +++ 48-1 ++ 49-1 + 50-1 ++ 52-1 ++++ 52-2 +52-3 ++++ 52-4 ++ 52-5 ++++ 52-6 ++++ 52-7 ++++ 52-8 ++++ 52-9 +++ 52-10++++ 52-11 ++++ 52-12 ++++ 52-13 +++++ 52-14 ++ 52-15 +++ 52-16 ++++52-17 +++ 52-18 +++ 52-19 +++ 52-20 ++++ 52-21 +++ 52-22 ++++ 52-23 ++++52-24 ++++ 52-25 +++ 52-26 ++++ 52-27 +++ 53-1 +++ 53-2 ++ 54-1 ++++54-2 +++++ 54-3 ++++ 54-4 +++++ 54-5 ++++ 54-6 +++ 54-7 ++++ 54-8 +++54-9 ++++ 54-10 +++ 54-11 + 55-1 ++++ 55-2 +++ 55-3 ++++ 56-1 ++++ 56-2+++++ 57-1 +++++ 58-1 +++ 58-2 +++ 59-1 +++ 60-1 ++++ 61-1 ++++ 62-1+++++ 63-1 ++++ 64-1 + 65-1 +++

Activity data for selected MRGPR X4 antagonists (versus 10 μM Bilirubinagonist, 20 μM deoxycholic acid, 100 μM conjugated bilirubin, 50 μMurobilin, or 20 μM obeticholic acid) are presented in Table 66B.

TABLE 66B IC₅₀ IC₅₀ IC₅₀ IC₅₀ (Conju- (Deoxy- IC₅₀ (Obeticholic(Bilirubin gated cholic Acid (Urobilin Acid Cpd agonist) Bilirubinagonist) Agonist) Agonist) No. nM Agonist) nM nM nM nM  1-55  6  14  2223 11  1-78  7  24  24 13 21  4-1 27  81  55 ND ND  1-115 81 180 230 ND47  1-18 57 130 130 230 40  1-29 20  46  46 16 25  1-56 28  32  30 21 24 1-65  9  17  28 21 23  1-85 20  29  30 41 15  4-10 16  21  22 35 15 4-11 24  41  63 35 25  1-101 17  12  75 91 22 42-3 16  28  16 21  717-4  5  7  6  6  8  1-31 10  9  5  7  5 32-1  6  7  10  8  3  5-1 10 27  23  6  6 ND = Not Determined

Example 67 Mouse Pharmacokinetics Studies

Compounds were formulated in 5% DMSO % Solutol, and 90% phosphatebuffered saline at a concentration of 5 mg/mL, and typically appeared asa fine homogenous suspension. Male C57BL/6 mice (n=3/compound) wereadministered a 50 mg/kg dose of each compound by oral gavage underanon-fasted condition. Blood samples were collected via the saphenousvein onto K2-EDTA at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after dosing,and plasma was prepared and stored at ≤60° C. until analysis. Plasmasample preparation for analysis was done by protein precipitation usingacetonitrile (including Celecoxib as an internal standard) followed bycentrifugation. Compound concentrations were determined in extractedplasma using LC-MS/MS relative to an 8 point standard curve covering the1 to 3000 ng/mL range. Non-compartmental analysis using PhoenixWinNonlin was used to estimate pharmacokinetic parameters including areaunder the curve, clearance, and half-life. The administered dose wasconfirmed by analysis of residual dosing material by UPLC-UV relative toa single point calibration sample. The results of these studies arepresented in Table 67.

TABLE 67 Cpd No. Cmax (μM) AUC (μMxhr) T-1/2 (hr)  1-18 113  376 4.2 1-115 306 1206 3.0  4-1 231 1503 5.9  1-29 196  615 4.6  1-55 230 215011.2   1-56 162  880 3.2  1-65 220 1037 4.8  1-78  57  219 4.0  1-85 2391069 4.7  4-10 260  974 4.6  4-11 257  572 3.6  1-101 230 1200 4.8 42-3460 4700 5.4

Example 68 Urobilin is a Potent MRGPRX4 Agonist and Pruritogen

Plasma urobilin is an oxidative product of the heme metaboliteurobilinogen. Urobilinogen is a by-product of bilirubin reduction in theintestines. Some of urobilinogen remains in the large intestine, whereit is converted to stercobilin. Some urobilinogen is reabsorbed into thebloodstream and delivered to the kidney, where it is oxidized tourobilin upon exposure to air.

Metabolites of heme (bilirubin, biliverdin, urobilin, urobilinogen, andstercobilin) were analyzed for in vitro activation of MRGPRX4. Cellswere plated in a 384-well assay plate at 20,000 cells per well in 12 μLof Opti-MEM and kept in an incubator overnight. On the day of the assay,different agonists solubilized at 10 mM in 0.1% NaOH were added as a10-point curve (10 mM final top concentration with 1:3 serial dilutions)using a Tecan D300E digital dispenser. Agonists were diluted in assaybuffer (final concentrations of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl,pH=8) and 2 μL of the appropriate agonist are added to each well. Plateswere incubated in the dark for 1 h at 37° C. and then for 30 minutes atroom temperature. IP-1 standards and HTRF detection reagents were addedaccording to the IP-One-Gq Kit purchased from Cisbio (part number62IPAPEJ) and incubated in the dark for 1 h at room temperature. Theplate was read on a Molecular Devices SpectraMax iD5 plate reader. TheHTRF ratio was calculated from the raw data and graphed using GraphPadPrism to calculate an IC50 value for each compound.

The results of this study are shown in FIG. 1. Urobilin was shown to beat least 10-fold more efficacious at activating MRGPRX4 than bilirubin.

The ability of urobilin to induce itch in wild type mice was alsotested. Typical mouse itch studies occurred as follows: C57B6J male micewere multiple-housed in a normal light cycle (6 am on; 6 pm off) undertemperature and humidity-controlled conditions. The mice were handledand habituated to test chambers before testing, then placed inindividual SCLABA test chambers. After 20 minutes, the mice were dosedPO with vehicle (saline, pH 7-8). After 30 minutes, the pruritogen ofstudy (100 mL in saline) or saline is given subcutaneously (SC) on theneck on the midline behind the ears. Video was recorded from the firstpruritogen injection for 30 minutes using the SCLABA system. Scratchingbouts were scored from SCLABA thumbnails using 12/45/85/100 waveformcriteria. Group sizes were typically 9-10 animals per group.

As shown in FIG. 2A, urobilin induced scratch response in mice in a dosedependent manner. Itch induction of urobilin was also compared todeoxycholic acid agonist and bilirubin agonist. As shown in FIG. 2B,urobilin is a potent inducer of scratch response in mice.

Example 69 Bilirubin and Urobilin can be Degraded by Light, Reducingtheir Agonist Activity on MRGPRX4

Bilirubin and Urobilin are agonists of MRGPRX4 that have beendemonstrated to be active pruitogens. Light therapy has been shown toreduce itch in cholestatic pruitis patients, which has been attributedto light-induced decomposition or chemical modification of bilirubin. Tofurther explore the contribution of light degradation toward thereduction of MRGPRX4 agonism, bilirubin and urobilin were pre-treatedwith different lighting and their activities were measured.

Stock solutions of both bilirubin and urobilin were made at 210 μM in0.1N NaOH (aq). Samples were stored either at room temperature in thedark, in a −20° C. freezer in the dark, room temperature on thecountertop under normal, lab lighting conditions, or at room temperatureunder a 400 nM blue-light lamp (similar to medical lamps used fortreating jaundice). Samples were evaluated after 24 hours and thepercent remaining of urobilin and bilirubin, relative to a time zerostandard, were determined by measurement of the degradation of theanalyte contained in the samples as determined by tandem massspectroscopy (LC MS/MS). The samples (at 24 h) were also evaluated fortheir ability to agonize MRGPRX4.

After 24 h, the freezer stock showed the highest amount of bilirubinremaining (44% of time zero), whereas all other conditions (roomtemperature dark, room temperature lab light, and room temperature bluelight) did not have any detectable bilirubin remaining. (FIG. 3A). Allsamples that were stored at room temperature (dark, room light and bluelight) showed significantly decreased agonist activity relative to thefrozen sample. (FIG. 3B)

Urobilin exhibited more stability than bilirubin, but degradation wasstill observed for all conditions. After 24 h, the sample stored in thedark had the highest remaining amount of urobilin relative to the timezero measurement (40%), while the freezer sample in the dark only had21% remaining. The room temperature sample under ambient lighting had34% remaining, but the room temperature sample under blue light had nodetectable urobilin remaining, indicating a higher vulnerability to thatwavelength of light. (FIG. 4A) The blue-light sample demonstrated verylittle agonist activity relative to the other three groups that wereexamined (room temp dark, frozen dark, and room temp light),corresponding to the measured remaining urobilin in those samples. (FIG.4B)

Example 70 Agonism of MRGPRX4 by an FXR Agonist can be Blocked byRepresentative MRGPRX4 Antagonists

BAR502, a dual FXR and GPBAR1 agonist also has agonist activity (5700nM) against MRGPRX4. Activity data for selected MRGPRX4 antagonistsversus 10 μM BAR502 in Table 70 show a range of antagonism from 11 to 48nM.

TABLE 70 Cpd No. IC₅₀ (10 μM BAR502) nM  1-18 48  1-55 16  1-56 16  1-6513  1-78 20 32-2 17 42-3 17  1-31 11

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety. In addition, the terms used in the following claimsshould not be construed as limited to the specific embodiments disclosedin the specification but should be construed to include all possibleembodiments along with the full scope of equivalents to which suchclaims are entitled.

1. A method for modulating a Mas-Related G-Protein Receptor (MRGPR) X4by contacting the MRGPRX4 with an effective amount of a compound havingthe structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein: n is 0 or 1; x is 0, 1 or 2; A isaryl or heteroaryl; Q₁ and Q₂ are both CR¹⁰, or one of Q₁ or Q₂ is CR¹⁰and the other is N; Z is —O—, —S—, —N(R¹¹)—, —CH₂— or —C≡C—; each R¹⁰ isH or alkyl; R is —(CH₂)_(m)C(═O)OR¹², —(CH₂)_(m)NHR¹³, —(C═O)NR¹⁴R¹⁵,—CH₂OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acidisostere; m is 0 or 1; R¹¹, R¹² and R¹³ are the same or different andindividually H or alkyl; R¹⁴ is H and R¹⁵ is H, —SO₂CH₃, carbocycle,heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selectedfrom —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle,or heterocycle, wherein R′ and R″ are individually H or alkyl, or R¹⁴and R¹⁵ are taken together with the nitrogen atom to which they areattached to form heterocycle; R¹ is H or alkyl; R² is halo, cyano,amino, alkyl, alkoxy, carbocycle or heterocycle; R³, R⁴ and R⁵ are thesame or different and either absent or, when present, cyano, nitro,halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl,—(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle,or any two R and R² taken together with the atoms to which they areattached form heterocycle; any two R³, R⁴, R⁵ and R¹⁰, taken togetherwith the atoms to which they are attached form carbocycle orheterocycle; and wherein each occurrence of carbocycle or heterocycle issubstituted with 0, 1, 2 or 3 substituents individually selected fromhalogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,carbocycle, or heterocycle.
 2. A method for treating an MRGPR X4dependent condition by administering to a subject in need thereof aneffective amount of a compound having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein: n is 0 or 1; x is 0, 1 or 2; A isaryl or heteroaryl; Q₁ and Q₂ are both CR¹⁰, or one of Q₁ or Q₂ is CR¹⁰and the other is N; Z is —O—, —S—, —N(R¹¹)—, —CH₂— or —C≡C—; each R¹⁰ isH or alkyl; R is —(CH₂)_(m)C(═O)OR¹², —(CH₂)_(m)NHR¹³, —(C═O)NR¹⁴R¹⁵,—CH₂OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acidisostere; m is 0 or 1; R¹¹, R¹² and R¹³ are the same or different andindividually H or alkyl; R¹⁴ is H and R¹⁵ is H, —SO₂CH₃, carbocycle,heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selectedfrom —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle,or heterocycle, wherein R′ and R″ are individually H or alkyl, or R¹⁴and R¹⁵ are taken together with the nitrogen atom to which they areattached to form heterocycle; R¹ is H or alkyl; R² is halo, cyano,amino, alkyl, alkoxy, carbocycle or heterocycle; R³, R⁴ and R⁵ are thesame or different and either absent or, when present, cyano, nitro,halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl,—(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle,or any two R and R² taken together with the atoms to which they areattached form heterocycle; any two R³, R⁴, R⁵ and R¹⁰, taken togetherwith the atoms to which they are attached form carbocycle orheterocycle; and wherein each occurrence of carbocycle or heterocycle issubstituted with 0, 1, 2 or 3 substituents individually selected fromhalogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,carbocycle, or heterocycle.
 3. The method of claim 2, wherein the MRGPRX4 dependent condition is a condition that is caused by the activationof MRGPR X4 by a bile acid or analog thereof.
 4. The method of claim 2wherein the MRGPR X4 dependent condition is an itch associatedcondition, a pain associated condition, or an autoimmune disorder. 5.The method of claim 4 wherein the itch associated condition is chronicitch, cholestatic pruritus, contact dermatitis, allergic blepharitis,anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chicken pox,cholestasis, end-stage renal failure, hemodialysis, contact dermatitis,dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidroticdermatitis, ectopic eczema, eczema, erythrasma, folliculitis, fungalskin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease,hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liverdisease, lymphoma, malignancy, multiple myeloma, neurodermatitis,onchocerciasis, Paget's disease, pediculosis, polycythemia rubra vera,pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies,schistosomiasis, scleroderma, severe stress, stasia dermatitis,swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, orurticaria.
 6. The method of claim 5 wherein the itch associatedcondition is cholestatic pruritus, uremic pruritus, atopic dermatitis,dry skin, psoriasis, contact dermatitis, or eczema.
 7. The method ofclaim 5, wherein the itch associated condition is a liver disease,wherein the liver disease is primary biliary cholangitis, primarysclerosing cholangitis, Alagille syndrome, Progressive familialintrahepatic cholestasis, Intrahepatic cholestasis of pregnancy,nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease(NAFLD), biliary atresia, chronic B hepatitis, drug-chronic viralhepatitis, induced liver injury (DILI), liver fibrosis, cholestaticliver disease, or alcoholic liver disease.
 8. The method of claim 2,further comprises administering to the subject a pharmaceuticallyeffective amount of a second therapeutic agent.
 9. The method of claim8, wherein the MRGPR X4 dependent condition is a liver disease and thesecond therapeutic agent is ursodeoxycholic acid (UDCA),norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone,rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin,fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine,metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR)agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, athyroid hormone receptor beta (TRβ) agonist, or any combination thereof.10. The method of claim 9, wherein the FXR agonist is obeticholic acid,Turofexorate isopropyl (WAY-362450),3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole(GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101,altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl,fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor(GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023,AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480,INV-33, RDX023-02, or any combination thereof.
 11. The method of claim9, wherein the PPAR agonist is a PPAR-alpha agonist, a PPAR-gammaagonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPARalpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPARalpha/gamma/delta pan agonist, optionally wherein: the PPAR alphaagonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil,clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate,pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, or SRI0171; the PPAR gamma agonist is rosiglitazone, pioglitazone,deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405,CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, orALL-4; the PPAR delta agonist is GW501516 (endurabol or({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (seladelpar or{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceticacid), GW0742([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy] acetic acid), L165041, HPP-593, or NCP-1046; the PPARalpha/gamma agonist is saroglitazar, aleglitazar, muraglitazar,tesaglitazar, or DSP-8658; the PPAR alpha/delta agonist is elafibranoror T913659; the PPAR gamma/delta agonist is a conjugated linoleic acid(CLA) or T3D-959; and the PPAR alpha/gamma/delta agonist is IVA337(lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148,GW9135, bezafibrate, lobeglitazone,2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoicacid (MHY2013), or CS038.
 12. The method of claim 9, wherein the TROagonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809,KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid],MB07811(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane),or any combination thereof.
 13. The method of claim 4 wherein the painassociated condition is acute pain, advanced prostate cancer,AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis,arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis,avascular necrosis, back pain, Behcet's disease (syndrome), burningmouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equinasyndrome, central pain syndrome, cerebral palsy, cervical stenosis,Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS),chronic functional abdominal pain (CFAP), chronic pain, chronicpancreatitis, collapsed lung (pneumothorax), complex regional painsyndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerativedisc disease, Dercum's disease, dermatomyositis, diabetic peripheralneuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis,eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia,gout, headaches, herniated disc, hydrocephalus, intercostal neuraligia,interstitial cystitis, irritable bowel syndrome (IBS), juveniledermatositis, knee injury, leg pain, loin pain-haematuria syndrome,lupus, lyme disease, medullary sponge kidney (MSK), meralgiaparesthetica, mesothelioma, migraine, musculoskeletal pain, myofascialpain, myositis, neck pain, neuropathic pain, occipital neuralgia,osteoarthritis, Paget's disease, Parsonage Turner syndrome, pelvic pain,peripheral neuropathy, phantom limb pain, pinched nerve, polycystickidney disease, polymyalgia rhuematica, polymyositis, porphyria, postherniorraphy pain syndrome, post mastectomy pain syndrome, post strokepain, post thorocotomy pain syndrome, postherpetic neuralgia (Shingles),post-polio syndrome, primary lateral sclerosis, psoriatic arthritis,pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoidarthritis (RA), sacroiliac joint dysfunction, sarcoidosi, Scheuemann'skyphosis disease, sciatica, Scoliosis, shingles (Herpes Zoster),Sjogren's syndrome, spasmodic torticollis, sphincter of oddidysfunction, spinal cerebellum ataxia (SCA ataxia), spinal cord injury,spinal stenosis, syringomyelia, tarlov cysts, transverse myelitis,trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascularpain or vulvodynia.
 14. The method of claim 4 wherein the autoimmunedisorder is chronic inflammation, multiple sclerosis, Steven Johnson'ssyndrome, appendicitis, bursitis, colitis, cystitis, dermatitis,phlebitis, reflex sympathetic dystrophy/complex regional pain syndrome(rsd/crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, reactiveairway disorder, asthma, airway infection, autoinflammatory disease,celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis,hidradenitis suppurativa, hypersensitivities, intestinal disorder,epithelial intestinal disorder, inflammatory bowel disease, irritablebowel syndrome, colitis, interstitial cystitis, otitis, pelvicinflammatory disease, endometrial pain, reperfusion injury, rheumaticfever, rheumatoid arthritis, sarcoidosis, transplant rejection, orvasculitis.
 15. The method of any one of claims 1-14, wherein thecompound has the structure of a compound listed Table A or B, or apharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,or salt thereof.
 16. A pharmaceutical composition comprising a compoundhaving the structure of Formula (I), or a pharmaceutically acceptableisomer, racemate, hydrate, solvate, isotope, or salt thereof, and apharmaceutically acceptable excipient:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope, or salt thereof, wherein: n is 0 or 1; x is 0, 1 or 2; A isaryl or heteroaryl; Q₁ and Q₂ are both CR¹⁰, or one of Q₁ or Q₂ is CR¹⁰and the other is N; Z is —O—, —S—, —N(R¹¹)—, —CH₂— or —C≡C—; each R¹⁰ isH or alkyl; R is —(CH₂)_(m)C(═O)OR¹², —(CH₂)_(m)NHR¹³, —(C═O)NR¹⁴R¹⁵,—CH₂OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acidisostere; m is 0 or 1; R¹¹, R¹² and R¹³ are the same or different andindividually H or alkyl; R¹⁴ is H and R¹⁵ is H, —SO₂CH₃, carbocycle,heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selectedfrom —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO₂OH, alkoxy, carbocycle,or heterocycle, wherein R′ and R″ are individually H or alkyl, or R¹⁴and R¹⁵ are taken together with the nitrogen atom to which they areattached to form heterocycle; R¹ is H or alkyl; R² is halo, cyano,amino, alkyl, alkoxy, carbocycle or heterocycle; R³, R⁴ and R⁵ are thesame or different and either absent or, when present, cyano, nitro,halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl,—(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle,or any two R and R² taken together with the atoms to which they areattached form heterocycle; any two R³, R⁴, R⁵ and R¹⁰, taken togetherwith the atoms to which they are attached form carbocycle orheterocycle; and wherein each occurrence of carbocycle or heterocycle issubstituted with 0, 1, 2 or 3 substituents individually selected fromhalogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,carbocycle, or heterocycle.
 17. The pharmaceutical composition of claim16, further comprising a second therapeutic agent.
 18. Thepharmaceutical composition of claim 17, wherein the second therapeuticagent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid,cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate(AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate,metronidazole, methotrexate, colchicine, metformin, betaine, glucagon,naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisomeproliferator-activated receptor (PPAR) agonist, a thyroid hormonereceptor beta (TRβ) agonist, or any combination thereof.
 19. Thepharmaceutical composition of claim 18, wherein: (a) the FXR agonist isobeticholic acid, Turofexorate isopropyl (WAY-362450),3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole(GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101,altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl,fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor(GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023,AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480,INV-33, RDX023-02, or any combination thereof, (b) the PPAR agonist is aPPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, aPPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPARgamma/delta dual agonist, or PPAR alpha/gamma/delta pan agonist,optionally wherein: the PPAR alpha agonist is fenofibrate, ciprofibrate,pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate,clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate,theofibrate, tocofibrate, or SRI 0171; the PPAR gamma agonist isrosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone,efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501,GED-0507-34-Levo, CLC-3001, or ALL-4; the PPAR delta agonist is GW501516(endurabol or{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (seladelpar or{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceticacid), GW0742([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy] acetic acid), L165041, HPP-593, or NCP-1046; the PPARalpha/gamma agonist is saroglitazar, aleglitazar, muraglitazar,tesaglitazar, or DSP-8658; the PPAR alpha/delta agonist is elafibranoror T913659; the PPAR gamma/delta agonist is a conjugated linoleic acid(CLA) or T3D-959; and the PPAR alpha/gamma/delta agonist is IVA337(lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148,GW9135, bezafibrate, lobeglitazone,2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoicacid (MHY2013), or CS038; or (c) the TRO agonist is sobetirome,eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid],MB07811(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane),or any combination thereof.
 20. A compound having one of the followingstructures, or a pharmaceutically acceptable isomer, racemate, hydrate,solvate, isotope, or salt thereof. Cpd No. Structure  1-55

 1-78

 5-1

 4-10

 1-65

 4-11

 1-58

 1-56

 9-1

 1-82

 1-85

 1-29

 1-101

 2-3

 1-103

 1-112

 4-7

11-1


21. A compound having one of the structures listed in Table A, or apharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,or salt thereof.
 22. A compound having one of the structures listed inTable B, or a pharmaceutically acceptable isomer, racemate, hydrate,solvate, isotope, or salt thereof.
 23. The method of claim 5 wherein theitch associated condition is kidney disease.
 24. The method of claim 23wherein kidney disease is end-stage renal failure.
 25. The method ofclaim 23 wherein kidney disease is medullary sponge kidney (MSK). 26.The method of claim 23 wherein kidney disease is polycystic kidneydisease.
 27. The method of claim 4 wherein the MRGPR X4 dependentcondition is an itch associated condition.
 28. The method of claim 27wherein the itch associated condition is associated with a metabolite ofheme.
 29. The method of claim 27 wherein the metabolite of heme isbilirubin.
 30. The method of claim 27 wherein the metabolite of heme isbiliverdin.
 31. The method of claim 27 wherein the metabolite of heme isurobilin.
 32. The method of claim 27 wherein the metabolite of heme isurobilinogen.
 33. The method of claim 27 wherein the metabolite of hemeis stercobilin.